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Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Marked gene: DNHD1 as ready
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Classified gene: DNHD1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.9 DNHD1 Zornitza Stark Gene: dnhd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark edited their review of gene: DNHD1: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v1.8 DNHD1 Zornitza Stark gene: DNHD1 was added
gene: DNHD1 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNHD1 were set to 34932939
Phenotypes for gene: DNHD1 were set to Spermatogenic failure 65, MIM# 619712
Added comment: Biallelic DNHD1 variants identified in 8 unrelated probands with asthenoteratozoospermia, reduced sperm motility and abnormal sperm morphology. DNHD1 knockout mice were infertile and had significantly reduced sperm concentration and motility rates, consistent with human individuals.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Marked gene: DNAH10 as ready
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Classified gene: DNAH10 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v1.7 DNAH10 Zornitza Stark Gene: dnah10 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v1.6 DNAH10 Zornitza Stark gene: DNAH10 was added
gene: DNAH10 was added to Infertility and Recurrent Pregnancy Loss. Sources: Expert list
Mode of inheritance for gene: DNAH10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH10 were set to 34237282
Phenotypes for gene: DNAH10 were set to Spermatogenic failure 56, MIM# 619515
Review for gene: DNAH10 was set to GREEN
Added comment: 4x families with 5 affecteds (chets and homs - 4 missense and 2 fs). Knockout mouse models were infertile and showed significant reduction in count and motility compared to heterozygous mice
Sources: Expert list
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Marked gene: ZNF597 as ready
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Classified gene: ZNF597 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v1.5 ZNF597 Zornitza Stark Gene: znf597 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Classified gene: SYCP3 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.4 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.3 SYCP3 Zornitza Stark reviewed gene: SYCP3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Classified gene: KPNA7 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v1.3 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v1.2 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, #MIM 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v1.2 GGN Zornitza Stark reviewed gene: GGN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v1.2 FOXD1 Zornitza Stark Phenotypes for gene: FOXD1 were changed from Recurrent pregnancy loss and repeated implantation failure susceptibility to Recurrent pregnancy loss and repeated implantation failure susceptibility, MONDO:0000144, FOXD1-related
Infertility and Recurrent Pregnancy Loss v1.1 ELL3 Zornitza Stark reviewed gene: ELL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v1.1 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew edited their review of gene: ZNF597: Changed publications: 19968752, 28157578, 32576657
Infertility and Recurrent Pregnancy Loss v1.0 ZNF597 Jasmine Chew gene: ZNF597 was added
gene: ZNF597 was added to Infertility and Recurrent Pregnancy Loss. Sources: Literature,Research
Mode of inheritance for gene: ZNF597 was set to Other
Publications for gene: ZNF597 were set to 28157578; 28157578; 2576657
Mode of pathogenicity for gene: ZNF597 was set to Other
Review for gene: ZNF597 was set to RED
Added comment: ZNF597 is an imprinted gene- maternally expressed and paternally imprinted.
- ZNF597 is highly expressed in the placenta and proposed to have an important role in placental development.
- Knockout ZNF597 mice (homozygous -/-) is embryonic lethal due to failed embryonic organization before cardiogenesis at embryonic day 7.5. This period is equivalent to human Carnegie Stage 9 that occurs during week 3 between 19 to 21 days (5 weeks' gestation).
- Literature associated with ZNF597 including maternal uniparental disomy of chromosome 16 (UPD(16)mat) or loss of paternal imprinting of ZNF59, resulting in an overexpression of ZNF597.
- Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy loss at 5-8 weeks' gestation.
Sources: Literature, Research
Infertility and Recurrent Pregnancy Loss v1.0 Zornitza Stark promoted panel to version 1.0
Infertility and Recurrent Pregnancy Loss v0.232 Zornitza Stark Panel name changed from Infertility and Pregnancy Loss to Infertility and Recurrent Pregnancy Loss
Panel status changed from internal to public
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Marked gene: NLRP14 as ready
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.231 NLRP14 Zornitza Stark Phenotypes for gene: NLRP14 were changed from Oocyte maturation defect and early embryo arrest to Inherited oocyte maturation defect, MONDO:0014769, NLRP14-related and early embryo arrest
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Marked gene: GALT as ready
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.230 GALT Zornitza Stark Phenotypes for gene: GALT were changed from Premature ovarian failure to Galactosaemia, MIM# 230400; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Classified gene: POLR3B as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.229 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Marked gene: POLG as ready
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.228 POLG Zornitza Stark Phenotypes for gene: POLG were changed from Premature ovarian failure to POLG-related disorders; Premature ovarian failure
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Classified gene: POLG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.227 POLG Zornitza Stark Gene: polg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Marked gene: MTHFR as ready
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.226 MTHFR Zornitza Stark Phenotypes for gene: MTHFR were changed from Recurrent pregnancy loss susceptibility to Homocystinuria due to MTHFR deficiency MIM#236250; Recurrent pregnancy loss susceptibility
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Classified gene: MTHFR as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.225 MTHFR Zornitza Stark Gene: mthfr has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Marked gene: LMNA as ready
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.224 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Female infertility, premature ovarian insufficiency to Laminopathy; Female infertility, premature ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Classified gene: LMNA as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.223 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Marked gene: IKBKG as ready
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Classified gene: IKBKG as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.222 IKBKG Zornitza Stark Gene: ikbkg has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 IKBKG Zornitza Stark Tag technically challenging tag was added to gene: IKBKG.
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Marked gene: CYP19A1 as ready
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Classified gene: CYP19A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.221 CYP19A1 Zornitza Stark Gene: cyp19a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Marked gene: CYP17A1 as ready
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Classified gene: CYP17A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.220 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Marked gene: ANKRD31 as ready
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Classified gene: ANKRD31 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.219 ANKRD31 Zornitza Stark Gene: ankrd31 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.218 ANKRD31 Zornitza Stark Phenotypes for gene: ANKRD31 were changed from Premature ovarian failure to Premature ovarian failure, MONDO:0019852, ANKRD31-related
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Marked gene: ACTL7A as ready
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Classified gene: ACTL7A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.217 ACTL7A Zornitza Stark Gene: actl7a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Marked gene: BCORL1 as ready
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.216 BCORL1 Zornitza Stark Phenotypes for gene: BCORL1 were changed from Spermatogenic failure to Spermatogenic failure, MONDO:0004983, BCORL1-related
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Classified gene: BCORL1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.215 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Marked gene: ANOS1 as ready
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.214 ANOS1 Zornitza Stark Publications for gene: ANOS1 were set to
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Classified gene: ANOS1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.213 ANOS1 Zornitza Stark Gene: anos1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Marked gene: ACTL9 as ready
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Classified gene: ACTL9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.212 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Marked gene: CHRNA1 as ready
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Classified gene: CHRNA1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.211 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 CHRNA1 Zornitza Stark reviewed gene: CHRNA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Marked gene: C4BPA as ready
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.210 C4BPA Zornitza Stark Phenotypes for gene: C4BPA were changed from recurrent pregnancy loss susceptibility to recurrent pregnancy loss susceptibility MONDO:0000144, C4BPA-related
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Classified gene: C4BPA as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.209 C4BPA Zornitza Stark Gene: c4bpa has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Marked gene: C14orf39 as ready
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Classified gene: C14orf39 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.208 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Marked gene: C17orf53 as ready
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.207 C17orf53 Zornitza Stark Publications for gene: C17orf53 were set to 34707299, 38105698,36099812; 31467087
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.206 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 C17orf53 Zornitza Stark Tag new gene name tag was added to gene: C17orf53.
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Marked gene: CLPP as ready
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Classified gene: CLPP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.205 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Marked gene: CLPB as ready
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Classified gene: CLPB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.204 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.203 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from Primary ovarian insufficiency to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Primary ovarian insufficiency
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Marked gene: CAPS as ready
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.202 CAPS Zornitza Stark Phenotypes for gene: CAPS were changed from Recurrent pregnancy loss to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CAPS-related
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Classified gene: CAPS as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.201 CAPS Zornitza Stark Gene: caps has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Marked gene: FKBP4 as ready
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.200 FKBP4 Zornitza Stark Phenotypes for gene: FKBP4 were changed from Recurrent pregnancy loss susceptibility to Recurrent pregnancy loss susceptibility, MONDO:0000144, FKBP4-related
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Classified gene: FKBP4 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.199 FKBP4 Zornitza Stark Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Classified gene: NOTCH2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.198 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Gene: notch2 has been removed from the panel.
Infertility and Recurrent Pregnancy Loss v0.197 NOTCH2 Zornitza Stark Phenotypes for gene: NOTCH2 were changed from Primary ovarian insufficiency to Inherited primary ovarian failure, MONDO:0019852, NOTCH2-related
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Classified gene: BRCA2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.196 BRCA2 Zornitza Stark Gene: brca2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 BRCA2 Zornitza Stark reviewed gene: BRCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Marked gene: FANCM as ready
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Classified gene: FANCM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.195 FANCM Zornitza Stark Gene: fancm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Marked gene: BNC1 as ready
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Classified gene: BNC1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.194 BNC1 Zornitza Stark Gene: bnc1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Marked gene: BLM as ready
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Classified gene: BLM as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.193 BLM Zornitza Stark Gene: blm has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.192 DCAF17 Zornitza Stark Phenotypes for gene: DCAF17 were changed from Hypergonadotropic/ Hypogonadotropic Hypogonadism to Woodhouse-Sakati syndrome, MIM# 241080; Hypergonadotropic/ Hypogonadotropic Hypogonadism
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Classified gene: DCAF17 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.191 DCAF17 Zornitza Stark Gene: dcaf17 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Marked gene: HSF2BP as ready
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Classified gene: HSF2BP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.190 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Marked gene: KIAA1683 as ready
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Classified gene: KIAA1683 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.189 KIAA1683 Zornitza Stark Gene: kiaa1683 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Marked gene: KCNU1 as ready
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.188 KCNU1 Zornitza Stark Publications for gene: KCNU1 were set to 34980136, 35551387; 20138882; 21427226; 25271166; 35551387
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Classified gene: KCNU1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.187 KCNU1 Zornitza Stark Gene: kcnu1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Marked gene: MSH5 as ready
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Classified gene: MSH5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.186 MSH5 Zornitza Stark Gene: msh5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Marked gene: PIEZO1 as ready
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Classified gene: PIEZO1 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.185 PIEZO1 Zornitza Stark Gene: piezo1 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 PIEZO1 Zornitza Stark reviewed gene: PIEZO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.184 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Meckel syndrome 12, MIM# 616258
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Classified gene: KIF14 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.183 KIF14 Zornitza Stark Gene: kif14 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Marked gene: WT1 as ready
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.182 WT1 Zornitza Stark Phenotypes for gene: WT1 were changed from Primary ovarian failure, MONDO:0005387 to Primary ovarian failure, MONDO:0005387, WT1-related
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Classified gene: WT1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.181 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.180 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Primary ovarian failure to Congenital disorder of glycosylation, type Ia, MIM #212065; Primary ovarian failure
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Classified gene: PMM2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.179 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Marked gene: POR as ready
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Classified gene: POR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.178 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Marked gene: RNF212B as ready
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.177 RNF212B Zornitza Stark Phenotypes for gene: RNF212B were changed from Female and male infertility with recurrent medically assisted reproduction (MAR) failures. to Infertility disorder, MONDO:0005047, RNF212B-related; Female and male infertility with recurrent medically assisted reproduction (MAR) failures.
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Classified gene: RNF212B as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.176 RNF212B Zornitza Stark Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Marked gene: SCN5A as ready
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Classified gene: SCN5A as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.175 SCN5A Zornitza Stark Gene: scn5a has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SCN5A Zornitza Stark reviewed gene: SCN5A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Classified gene: SEMA3A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.174 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Marked gene: SYCP2L as ready
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Classified gene: SYCP2L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.173 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Marked gene: SYCE1 as ready
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Classified gene: SYCE1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.172 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Classified gene: TAC3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.171 TAC3 Zornitza Stark Gene: tac3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Marked gene: TP63 as ready
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Classified gene: TP63 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.170 TP63 Zornitza Stark Gene: tp63 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Marked gene: SYCP2 as ready
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Classified gene: SYCP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.169 SYCP2 Zornitza Stark Gene: sycp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Marked gene: TLE6 as ready
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Classified gene: TLE6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.168 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Marked gene: TIMP2 as ready
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.167 TIMP2 Zornitza Stark Phenotypes for gene: TIMP2 were changed from Recurrent pregnancy loss susceptibility, MONDO:0000144 to Recurrent pregnancy loss susceptibility, MONDO:0000144, TIMP2-related
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Classified gene: TIMP2 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.166 TIMP2 Zornitza Stark Gene: timp2 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Marked gene: REC114 as ready
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Classified gene: REC114 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.165 REC114 Zornitza Stark Gene: rec114 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Marked gene: SYCP3 as ready
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Classified gene: SYCP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.164 SYCP3 Zornitza Stark Gene: sycp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Marked gene: TACR3 as ready
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Classified gene: TACR3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.163 TACR3 Zornitza Stark Gene: tacr3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Marked gene: TBPL2 as ready
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.162 TBPL2 Zornitza Stark Phenotypes for gene: TBPL2 were changed from Oocyte maturation arrest to Inherited oocyte maturation defect, MONDO:0014769, TBPL2-related
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Classified gene: TBPL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.161 TBPL2 Zornitza Stark Gene: tbpl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Marked gene: LHB as ready
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Classified gene: LHB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.160 LHB Zornitza Stark Gene: lhb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Marked gene: GNRH1 as ready
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Classified gene: GNRH1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.159 GNRH1 Zornitza Stark Gene: gnrh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Marked gene: TRIP13 as ready
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Classified gene: TRIP13 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.158 TRIP13 Zornitza Stark Gene: trip13 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Marked gene: TTN as ready
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Classified gene: TTN as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.157 TTN Zornitza Stark Gene: ttn has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 TTN Zornitza Stark reviewed gene: TTN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Lethal congenital contracture syndrome, MONDO:0017436; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Marked gene: WDR11 as ready
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Classified gene: WDR11 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.156 WDR11 Zornitza Stark Gene: wdr11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Marked gene: WEE2 as ready
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Classified gene: WEE2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.155 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.154 ATG4D Zornitza Stark Publications for gene: ATG4D were set to
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark edited their review of gene: ATG4D: Changed publications: 33988247; Changed phenotypes: Spermatogenic failure 101, MIM# 621269
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Gene: atg4d has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Classified gene: ATG4D as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.153 ATG4D Zornitza Stark Gene: atg4d has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.152 ATG4D Zornitza Stark gene: ATG4D was added
gene: ATG4D was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATG4D were set to Spermatogenic failure 101, MIM# 621269
Review for gene: ATG4D was set to AMBER
Added comment: 4 individuals from 3 unrelated families, all variants are missense, limited functional data.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 KCNU1 Jasmine Chew edited their review of gene: KCNU1: Changed publications: 34980136, 35551387, 20138882, 21427226, 25271166, 35551387
Infertility and Recurrent Pregnancy Loss v0.151 KCNU1 Jasmine Chew gene: KCNU1 was added
gene: KCNU1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KCNU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNU1 were set to 34980136, 35551387; 20138882; 21427226; 25271166; 35551387
Phenotypes for gene: KCNU1 were set to Spermatogenic failure 79, #MIM 620196
Review for gene: KCNU1 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 34980136, 35551387- 3 unrelated male with spermatogenic failure with different homozygous variants, supported by functional evidence; PubMed: 20138882, 21427226, 25271166- Slo3 -/- KO mice were infertile, 35551387- mice with homozygous H720R variant, corresponding to the human H715R variant recapitulated human phenotype.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 KIAA1683 Jasmine Chew gene: KIAA1683 was added
gene: KIAA1683 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KIAA1683 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1683 were set to 36321563; 39872118; 37140151; 37184908; 40437858
Phenotypes for gene: KIAA1683 were set to Spermatogenic failure 78, #MIM 620170
Review for gene: KIAA1683 was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 36321563, 39872118, 37140151, 37184908 (>3 unrelated Chinese men with infertility due to spermatogenic failure with hom/com het variants)

New paper:
i) PMID: 40437858 (2025)- novel hom p.Trp796Ter in infertile man with fertilization failure and history of two miscarriages with his partner. According to the prediction of protein conformations, it was found that the protein conformations were truncated in the mutated IQCN gene, which probably affected the function of the patient's sperm.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL9 Jasmine Chew gene: ACTL9 was added
gene: ACTL9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to 33626338; 38963606
Phenotypes for gene: ACTL9 were set to Spermatogenic failure 53, MIM# 619258
Review for gene: ACTL9 was set to GREEN
Added comment: Literature in OMIM entry- PMID: 33626338 (3 unrelated Chinese men with infertility due to spermatogenic failure with 2 hom missense variants, supported by functional evidence)

Other papers:
i) PMID: 38963606 (2024)- novel homozygous p.Gly342Cys and p.Val380Leu sitting in the actin domain in two independent Chinese families. Spermatozoa with ACTL9 mutations showed decreased CASA parameters and a higher proportion of spermatozoa with abnormal morphology, exhibiting coiled flagella and a thickened midpiece. The spermatozoa were characterized by chaotic or irregular '9+2' structures and irregular mitochondrial sheath arrangements in the flagellum. There was no significant difference in ACTL9 expression between the HeLa cells transfected with the WT and mutant ACTL9 plasmids. Actl9 knock-in mice also showed abnormal CASA parameters and irregular '9+2' structures in flagella.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL7A Jasmine Chew changed review comment from: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i)PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic. The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting, confirming the pathogenicity of the variants.

ii)PMID: 36574082 (2023)- two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Literature; to: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i) PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic.The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting.

ii)PMID: 36574082 (2023)- Two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 ACTL7A Jasmine Chew gene: ACTL7A was added
gene: ACTL7A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ACTL7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL7A were set to 32923619; 34727571; 36593593; 37004249; 37991128; 36574082; 35921706
Phenotypes for gene: ACTL7A were set to Spermatogenic failure 86, #MIM 620499
Review for gene: ACTL7A was set to GREEN
Added comment: Literature in OMIM entry- PubMed: 32923619, 34727571, 36593593, 37004249- different biallelic variants reported in >3 unrelated infertile men

Other papers:
i)PMID: 37991128 (2025)- two infertile males with com het p.R373H/p.G402S and hom p.R373C. All located within actin domain and predicted to be pathogenic. The protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting, confirming the pathogenicity of the variants.

ii)PMID: 36574082 (2023)- two infertile brothers with hom p.D75A with teratozoospermia and fertilization failure. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. The variant also caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients.

iii) PMID: 35921706 (2022)- Actl7a gene knockout (KO) mice led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Marked gene: TEX14 as ready
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Classified gene: TEX14 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.151 TEX14 Bryony Thompson Gene: tex14 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.150 TEX14 Bryony Thompson gene: TEX14 was added
gene: TEX14 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TEX14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEX14 were set to 16549803; 40492599; 28206990; 29790874; 36017582
Phenotypes for gene: TEX14 were set to Spermatogenic failure MONDO:0004983, TEX14-related
Review for gene: TEX14 was set to GREEN
Added comment: Multiple probands reported with biallelic LoF variants and a supporting mouse model.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Marked gene: CFAP221 as ready
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Classified gene: CFAP221 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.149 CFAP221 Zornitza Stark Gene: cfap221 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.148 CFAP221 Zornitza Stark gene: CFAP221 was added
gene: CFAP221 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CFAP221 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP221 were set to 31636325; 39362668; 40250778; 38960684; 40272718
Phenotypes for gene: CFAP221 were set to Ciliary dyskinesia, primary, 55, MIM# 279000
Review for gene: CFAP221 was set to GREEN
Added comment: Six affected families reported, male infertility is a feature.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.147 GALT Zornitza Stark Classified gene: GALT as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.147 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Marked gene: RNF216 as ready
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Gene: rnf216 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Classified gene: RNF216 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.146 RNF216 Zornitza Stark Gene: rnf216 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Marked gene: PABPC1L as ready
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Classified gene: PABPC1L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.145 PABPC1L Zornitza Stark Gene: pabpc1l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Marked gene: CCDC155 as ready
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Gene: ccdc155 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Classified gene: CCDC155 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.144 CCDC155 Zornitza Stark Gene: ccdc155 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.143 CCDC155 Zornitza Stark Tag new gene name tag was added to gene: CCDC155.
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Marked gene: TWNK as ready
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Gene: twnk has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Classified gene: TWNK as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.143 TWNK Zornitza Stark Gene: twnk has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Marked gene: FGF8 as ready
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Gene: fgf8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Classified gene: FGF8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.142 FGF8 Zornitza Stark Gene: fgf8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Marked gene: STIL as ready
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Gene: stil has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.141 STIL Zornitza Stark Phenotypes for gene: STIL were changed from Recurrent pregnancy loss susceptibility, MONDO:0000144; Primary microcephaly 7, autosomal recessive, MIM# 612703 to Primary microcephaly 7, autosomal recessive, MIM# 612703
Infertility and Recurrent Pregnancy Loss v0.140 STIL Zornitza Stark Classified gene: STIL as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.140 STIL Zornitza Stark Gene: stil has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.139 STIL Zornitza Stark reviewed gene: STIL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.139 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Marked gene: KISS1R as ready
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Gene: kiss1r has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Classified gene: KISS1R as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.139 KISS1R Zornitza Stark Gene: kiss1r has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Marked gene: CDC25A as ready
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.138 CDC25A Zornitza Stark Phenotypes for gene: CDC25A were changed from Spermatogenic failure to Spermatogenic failure, MONDO:0004983, CDC25A-related
Infertility and Recurrent Pregnancy Loss v0.137 CDC25A Zornitza Stark Classified gene: CDC25A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.137 CDC25A Zornitza Stark Gene: cdc25a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Marked gene: GNRHR as ready
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Gene: gnrhr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Classified gene: GNRHR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.136 GNRHR Zornitza Stark Gene: gnrhr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Marked gene: PREPL as ready
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Gene: prepl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.135 PREPL Zornitza Stark Phenotypes for gene: PREPL were changed from Hypergonadotropic hypogonadism to Myasthenic syndrome, congenital, 22, MIM# 616224; Hypergonadotropic hypogonadism
Infertility and Recurrent Pregnancy Loss v0.134 PREPL Zornitza Stark Classified gene: PREPL as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.134 PREPL Zornitza Stark Gene: prepl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Marked gene: SPEF2 as ready
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Classified gene: SPEF2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.133 SPEF2 Zornitza Stark Gene: spef2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Marked gene: PDCD2 as ready
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Classified gene: PDCD2 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.132 PDCD2 Zornitza Stark Gene: pdcd2 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.131 PDCD2 Zornitza Stark reviewed gene: PDCD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Marked gene: RXFP2 as ready
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.131 RXFP2 Zornitza Stark Phenotypes for gene: RXFP2 were changed from to Spermatogenic failure, MONDO:0004983, RXFP2-related
Infertility and Recurrent Pregnancy Loss v0.130 RXFP2 Zornitza Stark Classified gene: RXFP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.130 RXFP2 Zornitza Stark Gene: rxfp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Marked gene: ERCC6 as ready
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Classified gene: ERCC6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.129 ERCC6 Zornitza Stark Gene: ercc6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Marked gene: HARS2 as ready
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.128 HARS2 Zornitza Stark Publications for gene: HARS2 were set to 31449985,21464306, 34406847
Infertility and Recurrent Pregnancy Loss v0.127 HARS2 Zornitza Stark Classified gene: HARS2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.127 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Marked gene: FOXL2 as ready
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Classified gene: FOXL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.126 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.125 FOXL2 Zornitza Stark reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure 3, #MIM 608996; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Marked gene: PNPLA6 as ready
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Classified gene: PNPLA6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.125 PNPLA6 Zornitza Stark Gene: pnpla6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Marked gene: OOEP as ready
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Gene: ooep has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.124 OOEP Zornitza Stark Phenotypes for gene: OOEP were changed from Recurrent preimplantation embryonic arrest to Recurrent preimplantation embryonic arrest; Female infertility due to oocyte meiotic arrest, MONDO:0044626
Infertility and Recurrent Pregnancy Loss v0.123 OOEP Zornitza Stark Classified gene: OOEP as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.123 OOEP Zornitza Stark Gene: ooep has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Marked gene: PROK2 as ready
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Gene: prok2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Classified gene: PROK2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.122 PROK2 Zornitza Stark Gene: prok2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Marked gene: NUP107 as ready
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Classified gene: NUP107 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.121 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Marked gene: POLR3A as ready
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Gene: polr3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Classified gene: POLR3A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.120 POLR3A Zornitza Stark Gene: polr3a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Marked gene: DAP3 as ready
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Classified gene: DAP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.119 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Marked gene: LHX8 as ready
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Classified gene: LHX8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.118 LHX8 Zornitza Stark Gene: lhx8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Marked gene: MCM9 as ready
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Gene: mcm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Classified gene: MCM9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.117 MCM9 Zornitza Stark Gene: mcm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Marked gene: NBN as ready
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Classified gene: NBN as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.116 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Classified gene: NR0B1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.115 NR0B1 Zornitza Stark Gene: nr0b1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Marked gene: NLRP2 as ready
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Gene: nlrp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Classified gene: NLRP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.114 NLRP2 Zornitza Stark Gene: nlrp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Classified gene: NR5A1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.113 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Marked gene: MRPS22 as ready
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Gene: mrps22 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Classified gene: MRPS22 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.112 MRPS22 Zornitza Stark Gene: mrps22 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.111 MRPS22 Zornitza Stark reviewed gene: MRPS22: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ovarian dysgenesis 7, MIM# 618117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Marked gene: FGFR1 as ready
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Classified gene: FGFR1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.111 FGFR1 Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Marked gene: EIF2B5 as ready
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Gene: eif2b5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Classified gene: EIF2B5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.110 EIF2B5 Zornitza Stark Gene: eif2b5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Marked gene: MEIOB as ready
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Gene: meiob has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Classified gene: MEIOB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.109 MEIOB Zornitza Stark Gene: meiob has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Marked gene: EIF2B4 as ready
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Gene: eif2b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Classified gene: EIF2B4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.108 EIF2B4 Zornitza Stark Gene: eif2b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Marked gene: EIF2B2 as ready
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Gene: eif2b2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Classified gene: EIF2B2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.107 EIF2B2 Zornitza Stark Gene: eif2b2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Marked gene: GGPS1 as ready
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Classified gene: GGPS1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.106 GGPS1 Zornitza Stark Gene: ggps1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Marked gene: C11orf80 as ready
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.105 C11orf80 Zornitza Stark Publications for gene: C11orf80 were set to
Infertility and Recurrent Pregnancy Loss v0.104 C11orf80 Zornitza Stark Classified gene: C11orf80 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.104 C11orf80 Zornitza Stark Gene: c11orf80 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.103 C11orf80 Zornitza Stark Tag new gene name tag was added to gene: C11orf80.
Infertility and Recurrent Pregnancy Loss v0.103 CAPS Jasmine Chew changed review comment from: PMID: 30339840- Homozygous del p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Literature; to: PMID: 30339840- Homozygous p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CAPS Jasmine Chew gene: CAPS was added
gene: CAPS was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CAPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPS were set to 30339840
Phenotypes for gene: CAPS were set to Recurrent pregnancy loss
Review for gene: CAPS was set to AMBER
Added comment: PMID: 30339840- Homozygous del p.L127Wfs in a consanguineous family of 3 sisters with unexplained RPL. In vitro study also showed that mRNA expression of CAPS was downregulated in decidual and placental villous tissues of RPL patients, and CAPS expression in CAPS–homo-919–transfected cells showed a significant decrease compared with the other groups. Transwell assay with Matrigel also revealed that CAPS–homo-919 could affect JAR cell invasion compared with NC (P < 0.01), which might impair trophoblast infiltration ability. An enzyme-linked immunosorbent assay showed that CAPS–homo-919 could induce a dramatic increase in PGE2 release from the RL95-2 cells (P < 0.05), compared with NC.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MTHFR Jasmine Chew gene: MTHFR was added
gene: MTHFR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MTHFR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTHFR were set to 37260775; 39534907; 38322638
Phenotypes for gene: MTHFR were set to Recurrent pregnancy loss susceptibility
Review for gene: MTHFR was set to AMBER
Added comment: PMID: 37260775- RPL5 couple was found to be carriers for mutation in the MTHFR gene. It is already known that women with a MTHFR variant have a higher risk for pregnancy-related issues such as miscarriages, preeclampsia, or a baby born with birth defects, such as spina bifida. The theory behind the connection between the MTHFR mutation and pregnancy loss is that tiny blood clots are formed because of homocysteinemia, which blocks the flow of nutrition to the placenta, essentially starving the fetus and triggering a spontaneous abortion (Dell’dera et al., 2018- PMID: 29435277).

ii) PMID: 39534907- The MTHFR C677T variant showed strong associations with unexplained RPL, particularly the CT genotype (OR: 6.07, 95% CI: 3.00-12.93; p < 0.001) and TT genotype (OR: 14.62, 95% CI: 2.85-114.77; p = 0.003) in Vietnamese population.

iii) PMID: 38322638- 6.2% of couples with a history of RPL had MTHFR C677T in an Iranian population

Note: MTHFR is a thrombophilic marker and DNA methylation- PMID: 34745108).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FKBP4 Jasmine Chew gene: FKBP4 was added
gene: FKBP4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FKBP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FKBP4 were set to 31504499
Phenotypes for gene: FKBP4 were set to Recurrent pregnancy loss susceptibility
Review for gene: FKBP4 was set to AMBER
Added comment: i) PMID: 31504499- Four heterozygous missense variants (Ala16Glu, Asn125Ser, Gln381Leu, Arg399Gln) at conserved residues within two functional domains of FKBP52 identified in four different Asian patients with RPL. The variants were predicted to have damaging effects to structure-function properties and were shown to abrogate PPIase activity in a cell-based assay.
- Although FKBP4 heterozygous null animals were all fertile and without reproductive failures, both male and female homozygous mice were reported to be infertile, highlighting the importance of FKBP52 in reproduction. Interestingly, male null mice were found to produce viable spermatozoa but had defects in reproductive tissues consistent with androgen insensitivity. Female null mice were anatomically normal, but infertility was found to be a consequence of either implantation failure or pregnancy loss following implantation, which was associated with impaired progesterone function.
- There remains a possibility that this apparent population bias might suggest an Asian specific cause of RPL.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C4BPA Jasmine Chew changed review comment from: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q). l. The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution. R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls. However, they observed that homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Literature; to: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q).
- The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution.
R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls.
- Homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C4BPA Jasmine Chew gene: C4BPA was added
gene: C4BPA was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C4BPA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C4BPA were set to 23508668
Phenotypes for gene: C4BPA were set to recurrent pregnancy loss susceptibility
Review for gene: C4BPA was set to AMBER
Added comment: PMID: 23508668- Five unrelated female with history of recurrent RPL (<10 weeks) carrying het missnese variants (See table 3- G423E, R120H, I126T, P4Q). l. The I126T mutation in CCP2 of C4BP α-chain is of particular interest as it was found only in one patient but not in healthy controls. This rare mutation affected both expression level of C4BP α-chain as well as its function, i.e., degradation of C4b and C3b in solution. R120H, found in two patients and no controls, increased the ability of C4BP to act as cofactor in degradation of C4b but decreased its activity in degradation of C3b both in solution and deposited on the cell surface. The other 2 variants have been observed in controls. However, they observed that homozygous C4BP knockout mice often die during second or third pregnancy (unpublished observation). This would imply a pivotal role of this protein in maintenance of successful pregnancy, although the mechanism is not known.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DAP3 Jasmine Chew gene: DAP3 was added
gene: DAP3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Perrault syndrome 7, MIM# 621101
Review for gene: DAP3 was set to GREEN
Added comment: PMID: 39701103- biallelic variants in 3 unrelated patients. Proteomic analysis in patient fibroblasts showed reduced DAP3 expression, reduced expression of respiratory chain complexes I, III, and IV, and decreased expression of proteins encompassing the small mitoribosomal subunit complex. Patient fibroblasts transduced with wildtype DAP3 demonstrated partial rescue of mitoribosomal MRPS7 (611974) and MRPS9 (611975) protein levels.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPB Jasmine Chew gene: CLPB was added
gene: CLPB was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 36074910
Phenotypes for gene: CLPB were set to Primary ovarian insufficiency
Review for gene: CLPB was set to GREEN
Added comment: PMID: 36074910- A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CCDC155 Jasmine Chew changed review comment from: Note- HGNC Approved Gene Symbol: KASH5 (MIM #618125)

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410- Compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature; to: HGNC approved symbol- KASH5

Biallelic variants reported for POI- PMID: 35587281; 35674372; 35708642; 36864840

Biallelic variants reported for spermatogenic failure-PMID: 29790874; 35587281; 35674372; 36864840

Biallelic variants reported for recurrent miscarriages- PMID:36864840- The authors hypothesized that this reduced interaction with SUN1 might be sufficient to allow folliculogenesis and fertilization despite severe meiotic defects, and suggested that in addition to POF, KASH5 might represent a recurrent pregnancy loss-associated gene.

Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C17orf53 Jasmine Chew edited their review of gene: C17orf53: Changed publications: 34707299, 38105698, 36099812, 31467087
Infertility and Recurrent Pregnancy Loss v0.103 C17orf53 Jasmine Chew gene: C17orf53 was added
gene: C17orf53 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C17orf53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf53 were set to 34707299, 38105698,36099812; 31467087
Phenotypes for gene: C17orf53 were set to Ovarian dysgenesis 11, MIM# 620897
Review for gene: C17orf53 was set to GREEN
Added comment: HGNC approved symbol- HROB

Biallelic variants reported for POI- PMID: 34707299, 38105698,36099812

PMID: 31467087- Knockout mice were infertile due to lack of germ cells. The sterile females had ovaries that lacked follicles, whereas the sterile males had mostly empty seminiferous tubules, suggesting a defect in sperm production. Concluded that these phenotypes were consistent with a prophase I meiotic arrest.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BLM Jasmine Chew gene: BLM was added
gene: BLM was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLM were set to 34794894; 29056561; 28846287
Phenotypes for gene: BLM were set to Bloom syndrome, MIM# 210900
Review for gene: BLM was set to GREEN
Added comment: PMID: 28846287 (Gene Review)- Women may be fertile but often have early menopause, and men tend to be infertile. Most men with BSyn assessed for infertility have had azoospermia or severe oligospermia.

PMID: 35671666, PMID: 24858046- BLM physically interacts with MUS81, an endonuclease involved in the restart of stalled replication forks and HR repair. Loss of Mus81 in Blm hypomorph mutant mice leads to infertility, and growth and developmental defects that are not observed in single mutants. Double mutant cells and mice were hypersensitive to Mitomycin C and γ-irradiation (IR) compared with controls and their repair of DNA double-strand breaks (DSBs) mediated by HR pathway was significantly defective, whereas their non-homologous-end-joining repair was elevated compared with controls.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew changed review comment from: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754
Sources: Literature; to: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754; 16882753
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew edited their review of gene: ANOS1: Changed publications: 40508017, 40262549, 40258767, 40101754, 16882753
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew edited their review of gene: ANOS1: Changed publications: 40508017, 40262549, 40258767, 40101754
Infertility and Recurrent Pregnancy Loss v0.103 ANOS1 Jasmine Chew gene: ANOS1 was added
gene: ANOS1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ANOS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ANOS1 were set to Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), MIM# 308700
Review for gene: ANOS1 was set to GREEN
Added comment: Hemizygous variants reported for HH- PMID:40508017; 40262549; 40258767; 40101754
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 WDR11 Jasmine Chew edited their review of gene: WDR11: Changed publications: 20887964, 37988663, 36130823, 35722485, 32982993, 29263200
Infertility and Recurrent Pregnancy Loss v0.103 WDR11 Jasmine Chew gene: WDR11 was added
gene: WDR11 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: WDR11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR11 were set to 20887964, 37988663; 36130823; 35722485; 32982993; 29263200
Phenotypes for gene: WDR11 were set to Hypogonadotropic hypogonadism 14 with or without anosmia, MIM# 614858
Review for gene: WDR11 was set to GREEN
Added comment: Monoallelic variants reported for HH- PMID: 20887964, 37988663; 36130823; 35722485; 32982993

PMID: 29263200- Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TWNK Jasmine Chew gene: TWNK was added
gene: TWNK was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TWNK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TWNK were set to 28178980; 26970254; 25355836; 25355836; 32281099; 31852434; 31455392
Phenotypes for gene: TWNK were set to Perrault syndrome 5, MIM# 616138
Review for gene: TWNK was set to GREEN
Added comment: Ovarian dysgenesis is one of the phenotypes of Perrault syndrome.

FeRGI database- moderate evidence for POI (Perrault syndrome)- biallelic variants reported in multiple papers
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TP63 Jasmine Chew gene: TP63 was added
gene: TP63 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TP63 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TP63 were set to 30924587; 35801529; 36856110; 27798044
Phenotypes for gene: TP63 were set to Premature ovarian failure 21, MIM# 620311
Review for gene: TP63 was set to GREEN
Added comment: Monoallelic missense/LOF variants reported for POI- PMID: 30924587; 35801529;36856110
- PMID: 35801529;36856110- suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes.
- PMID:36856110- Heterozygous mutant females were infertile, whereas mutant males were fertile. Eexpression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype.

PMID: 27798044- monoallelic variants for Mullerian duct anomalies
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 SYCP2L Jasmine Chew gene: SYCP2L was added
gene: SYCP2L was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603; 38521400
Phenotypes for gene: SYCP2L were set to Premature ovarian failure 24, MIM# 620840
Review for gene: SYCP2L was set to GREEN
Added comment: Biallelic LOF/missense variants reported for POI- PMID:32303603; 38521400
- Sycp2l-deficient female mice are subfertile (PMID: 26362258). The association of the genes that have key roles in meiosis and DNA repair with POI has been previously reported (PMID: 32381463;34707299).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TACR3 Jasmine Chew gene: TACR3 was added
gene: TACR3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TACR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACR3 were set to 22031817; 20332248; 20194706; 20395662; 19755480; 28915117; 19079066
Phenotypes for gene: TACR3 were set to Hypogonadotropic hypogonadism 11 with or without anosmia, MIM# 614840
Review for gene: TACR3 was set to GREEN
Added comment: Biallelic variants reported for HH- PMID:22031817; 20332248; 20194706; 20395662; 19755480; 28915117; 19079066
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 TAC3 Jasmine Chew gene: TAC3 was added
gene: TAC3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TAC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAC3 were set to 20332248; 20194706; 34403359; 19079066
Phenotypes for gene: TAC3 were set to Hypogonadotropic hypogonadism 10 with or without anosmia, MIM# 614839
Review for gene: TAC3 was set to GREEN
Added comment: Biallelic variants reported for HH- PMID:20332248; 20194706; 34403359; 19079066
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 SEMA3A Jasmine Chew gene: SEMA3A was added
gene: SEMA3A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SEMA3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3A were set to 22416012; 22927827; 32060892; 31200363; 33819414
Phenotypes for gene: SEMA3A were set to Hypogonadotropic hypogonadism 16 with or without anosmia, MIM# 614897
Review for gene: SEMA3A was set to GREEN
Added comment: Monoallelic variants reported for HH/infertility- PMID:22416012; 22927827; 32060892;31200363;33819414
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 RNF216 Jasmine Chew gene: RNF216 was added
gene: RNF216 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: RNF216 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF216 were set to 31200363; 25841028; 39444518; 38050071
Phenotypes for gene: RNF216 were set to Cerebellar ataxia and hypogonadotropic hypogonadism, MIM# 212840
Review for gene: RNF216 was set to GREEN
Added comment: Biallelic variants reported for HH phenotype-PMID:31200363;25841028;39444518

PMID:38050071 (review paper, 2024)- Over 90% of individuals presented with cognitive impairment and hypogonadotropic hypogonadism throughout the disease. Male individuals seemed to be more vulnerable than female individuals. Most male individuals suffered from poor pubertal development. .This phenomenon was consistent with the results of previous animal experiments, whereby targeted deletion of the RNF216 gene in mice resulted in disruption in spermatogenesis and male infertility, but RNF216 was not required for female fertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PROK2 Jasmine Chew gene: PROK2 was added
gene: PROK2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PROK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PROK2 were set to 23341491; 18559922; 17959774; 17054399; 31200363; 33819414
Phenotypes for gene: PROK2 were set to Hypogonadotropic hypogonadism 4 with or without anosmia, MIM# 610628
Review for gene: PROK2 was set to GREEN
Added comment: FeRGI database- strong evidence for hypogonadotropic hypogonadism- PMID:23341491;18559922; 17959774;17054399;31200363;33819414 - monoallelic and biallelic variants reported.

PMID:17959774- Prok2 -/- mice also showed hypogonadotropic hypogonadism.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PREPL Jasmine Chew changed review comment from: Hypergonadotropic hypogonadism is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency.
Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803
Sources: Literature; to: Hypergonadotropic hypogonadism/POI is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency. Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PREPL Jasmine Chew gene: PREPL was added
gene: PREPL was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PREPL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PREPL were set to 34794894; 28726805; 30924587; 32218803
Phenotypes for gene: PREPL were set to Hypergonadotropic hypogonadism
Review for gene: PREPL was set to GREEN
Added comment: Hypergonadotropic hypogonadism is one of the phenotypes of prolyl endopeptidase-like (PREPL) deficiency.
Biallelic variants reported in patients with PREPL deficiency- PMID: 34794894;28726805;30924587;32218803
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POR Jasmine Chew gene: POR was added
gene: POR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POR were set to 32725309; 32242900
Phenotypes for gene: POR were set to Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM# 613571
Review for gene: POR was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:32725309, 32242900- biallelic variants reported for menstrual cycle disorders and female infertility. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew changed review comment from: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported
Sources: Literature; to: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported.
- PMID: 25339210 - delayed puberty or primary amenorrhea was present in 27/33 patients with POLR3A (81%).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew edited their review of gene: POLR3A: Changed publications: 23694757, 21855841, 30414627, 34611991, 25339210
Infertility and Recurrent Pregnancy Loss v0.103 POLR3A Jasmine Chew gene: POLR3A was added
gene: POLR3A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3A were set to 23694757; 21855841; 30414627; 34611991
Phenotypes for gene: POLR3A were set to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694
Review for gene: POLR3A was set to GREEN
Added comment: FeRGI database- moderate evidence for hypogonadotropic hypogonadism- biallelic variants reported
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PNPLA6 Jasmine Chew edited their review of gene: PNPLA6: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.103 PNPLA6 Jasmine Chew gene: PNPLA6 was added
gene: PNPLA6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to 27866050; 24790214; 25267340; 25033069; 24355708; 33141049
Phenotypes for gene: PNPLA6 were set to Boucher-Neuhauser syndrome, MIM# 215470
Added comment: Hypogonadotropic hypogonadism is a feature of Boucher-Neuhauser syndrome, MIM# 215470.

FeRGI database- Strong evidence for hypogonadotropic hypogonadism- multiple papers reported biallelic variants
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis- PMID: 26485283; 34707299; 29363275 (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158 - Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew changed review comment from: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158-Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature; to: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158- Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NUP107 Jasmine Chew gene: NUP107 was added
gene: NUP107 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NUP107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP107 were set to 26485283; 34707299; 29363275
Phenotypes for gene: NUP107 were set to Ovarian dysgenesis 6, MIM# 618078
Review for gene: NUP107 was set to GREEN
Added comment: FeRGI database- moderate evidence for ovarian dysgenesis (biallelic variants reported for ovarian dysgenesis/premature ovarian insufficiency)

https://mednexus.org/doi/full/10.4103/2096-2924.268158-Knockdown of NUP107 expression had little effect on the growth and number of human granulosa cell (GC). Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone (FSH) by decreasing the expression of estrogen synthesis-related genes AR, CYP17A1, CYP19A1, STAR, and NR5A1. Moreover, knockdown of NUP107 decreased the expression of AMHR2, FSHR, LHR, and ESR1 in GCs, but had no effect on the expression of ESR2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NOTCH2 Jasmine Chew gene: NOTCH2 was added
gene: NOTCH2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to 32312275; 30304577; 28505269; 28283672
Phenotypes for gene: NOTCH2 were set to Primary ovarian insufficiency
Review for gene: NOTCH2 was set to GREEN
Added comment: i) PMID: 32312275 -Heterozygous missense variant p.Asp1853His in both mother an daughter with POI. Cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. 106 protein-coding genes enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells.

ii) PMID: 30304577, 28505269 - 4 unrelated women with POI with heterozygous missense variants (p.Ser1804Leu, p.Gln1811His, p.Leu2408His, p.Pro2359Ala) and 1 woman with POI suspected biallelic (p.Ala2316Val & p.Leu2408His). NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. Suggested that POI is associated with loss of function of NOTCH2.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure/infertility has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed in individuals with biallelic variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure/infertility has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew changed review comment from: Premature ovarian failure has been observed.
Sources: Literature; to: Premature ovarian failure/infertility has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NBN Jasmine Chew gene: NBN was added
gene: NBN was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NBN were set to 19105185; 29706645; 31729086; 34794894; 20444919
Phenotypes for gene: NBN were set to Nijmegen breakage syndrome, MIM# 251260
Review for gene: NBN was set to GREEN
Added comment: Premature ovarian failure has been observed.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MRPS22 Jasmine Chew gene: MRPS22 was added
gene: MRPS22 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MRPS22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS22 were set to 29566152; 31042289
Phenotypes for gene: MRPS22 were set to Ovarian dysgenesis 7, MIM# 618117
Review for gene: MRPS22 was set to GREEN
Added comment: PMID:29566152, 31042289- Two homozygous missense variants (p.Arg202His and p.Arg135Gln) reported in independent families with POI. Mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, Drosophila model with mRpS22 deficiency specifically in germ cells were infertile and agametic. Heterozygous MRPS22 knockout mice are fertile and show no overt abnormalities. Homozygous MRPS22 knockout results in embryonic lethality.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew changed review comment from: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:25480036, 26771056, 31042289 (biallelic variants reported)
Sources: Literature; to: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:27802094, 25480036, 26771056, 31042289, 32145932 (monoallelic and biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew edited their review of gene: MCM9: Changed publications: 27802094, 25480036, 26771056, 31042289, 32145932; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.103 MCM9 Jasmine Chew gene: MCM9 was added
gene: MCM9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MCM9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM9 were set to 25480036; 26771056; 31042289
Phenotypes for gene: MCM9 were set to Ovarian dysgenesis 4, MIM# 616185
Review for gene: MCM9 was set to GREEN
Added comment: FeRGI database- definitive evidence for ovarian dysgenesis- PMID:25480036, 26771056, 31042289 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 LHX8 Jasmine Chew gene: LHX8 was added
gene: LHX8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX8 were set to 27603904; 34095689; 29329412; 36029299
Phenotypes for gene: LHX8 were set to Inherited premature ovarian failure, MONDO:0019852, LHX8-related
Review for gene: LHX8 was set to GREEN
Added comment: PMID:27603904; 34095689- reported POI patient with the same heterozygous missense p.Ala325Val variant.

PMID: 29329412 - Lhx8 knockout mouse model demonstrates that Lhx8-/- ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. Lhx8-/- oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development and DNA damage repair genes were downregulated throughout the oocyte short lifespan.

PMID: 36029299- 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families with infertility characterized by oocyte maturation arrest. All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 KISS1R Jasmine Chew gene: KISS1R was added
gene: KISS1R was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KISS1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KISS1R were set to 23349759; 22619348; 21193544; 17164310; 14573733; 27094476; 33819414
Phenotypes for gene: KISS1R were set to Hypogonadotropic hypogonadism 8 with or without anosmia, MIM# 614837
Review for gene: KISS1R was set to GREEN
Added comment: FeRGI database- Definitive evidence for hypogonadotropic hypogonadism- multiple papers reported biallelic variants.
- early miscarriages have been reported in couples with the male partner being a carrier of a KISS1R variant (PMID: 23349759)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HSF2BP Jasmine Chew changed review comment from: Sources: Literature; to: PMID:32845237, 35174157- Three different homozygous missense variants (S167L, C128R, p.L186P) reported in three independent families.
- HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers.
- C128R and p.L186P variants impaired the nuclear location of HSF2BP and affected its DNA repair capacity.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HSF2BP Jasmine Chew gene: HSF2BP was added
gene: HSF2BP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237; 35174157
Phenotypes for gene: HSF2BP were set to Premature ovarian failure 19, OMIM#619245
Review for gene: HSF2BP was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GGPS1 Jasmine Chew gene: GGPS1 was added
gene: GGPS1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32399598; 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, MMIM# 619518
Review for gene: GGPS1 was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:32399598, 32403198- biallelic variants reported. Also in mice, PMID: 32403198 found that homozygosity for the Y259C missense variant was embryonic lethal.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew changed review comment from: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic variants.
Sources: Literature; to: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic missense/LOF variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew edited their review of gene: FGFR1: Changed publications: 28008864, 26708526, 22035731, 21682876, 17154279, 16764984, 32485746; Changed phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia , MIM#147950
Infertility and Recurrent Pregnancy Loss v0.103 FGFR1 Jasmine Chew gene: FGFR1 was added
gene: FGFR1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGFR1 were set to 28008864; 26708526; 17154279; 21682876; 16764984
Phenotypes for gene: FGFR1 were set to Hypogonadotropic hypogonadism 2 with or without anosmia , MIM#147950
Review for gene: FGFR1 was set to GREEN
Added comment: FeRGI database- strong evidence for Hypogonadotropic hypogonadism- multiple literature reported monoallelic variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 FANCM Jasmine Chew gene: FANCM was added
gene: FANCM was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FANCM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCM were set to 33036707; 29231814; 30075111; 29895858; 38927643
Phenotypes for gene: FANCM were set to Premature ovarian failure 15, MIM# 618096; Spermatogenic failure 28, MIM# 618086
Review for gene: FANCM was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:33036707,29231814- biallelic variants reported

Evidence for Spermatogenic failure 28, MIM# 618086 (AR)- PMID: 30075111, 29895858, 38927643- biallelic variants in males with NOA/SCOS phenotypes
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ERCC6 Jasmine Chew gene: ERCC6 was added
gene: ERCC6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ERCC6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERCC6 were set to 26218421; 33109206; 33538981; 39277148; 35975393
Phenotypes for gene: ERCC6 were set to Premature ovarian failure 11, MIM# 616946
Review for gene: ERCC6 was set to GREEN
Added comment: FeRGI database- moderate evidence for POI- PMID:26218421, 33109206, 33538981 (heterozygous variants reported)

New papers:
i) PMID: 39277148- Two different missense p.Val127Ile and p.Glu1408 Ala in 4 POI patients with RNA and protein expression absent/decreased in patients.

ii) PMID: 35975393- A novel het p.GLy815Asp in a POI patient and Swiss-Model revealed that the mutant amino acid formed multiple H-bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew changed review comment from: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature; to: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew changed review comment from: FeRGI db-Strong for POI (Woodhouse-Sakati syndrome)- biallelic variants reported in multiple literature- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature; to: FeRGI db- Strong for POI (Woodhouse-Sakati syndrome, MIM#241080)- biallelic variants reported in multiple literature with hypogonadism as one of the phenotypes- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 DCAF17 Jasmine Chew gene: DCAF17 was added
gene: DCAF17 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DCAF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF17 were set to 33819414; 27240811; 20507343; 34630532; 31347785; 34590781; 29574468
Phenotypes for gene: DCAF17 were set to Hypergonadotropic/ Hypogonadotropic Hypogonadism
Review for gene: DCAF17 was set to GREEN
Added comment: FeRGI db-Strong for POI (Woodhouse-Sakati syndrome)- biallelic variants reported in multiple literature- https://www.eshre.eu/Files/Fergi/DCAF17_var.pdf
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew changed review comment from: FeRGI database- Strong evidence for POI (Perrault syndrome 3- premature ovarian failure (POF) secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature; to: FeRGI database- Strong evidence for POI (Perrault syndrome 3- POI secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew changed review comment from: FeRGI database- Strong evidence for POI (Perrault syndrome 3)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature; to: FeRGI database- Strong evidence for POI (Perrault syndrome 3- premature ovarian failure (POF) secondary to ovarian dysgenesis)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 CLPP Jasmine Chew gene: CLPP was added
gene: CLPP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27087618; 23541340; 32399598; 33538981
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
Added comment: FeRGI database- Strong evidence for POI (Perrault syndrome 3)- PMID:27087618, 23541340,32399598,33538981 (biallelic variants reported)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 C14orf39 Jasmine Chew gene: C14orf39 was added
gene: C14orf39 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C14orf39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C14orf39 were set to 33508233; 34718620; 27796301
Phenotypes for gene: C14orf39 were set to Premature ovarian failure 18, MIM# 619203; Spermatogenic failure 52, MIM# 619202
Review for gene: C14orf39 was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BRCA2 Jasmine Chew edited their review of gene: BRCA2: Changed publications: 32482800, 30207912, 30865812
Infertility and Recurrent Pregnancy Loss v0.103 BRCA2 Jasmine Chew gene: BRCA2 was added
gene: BRCA2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BRCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRCA2 were set to 32482800; 30207912
Phenotypes for gene: BRCA2 were set to Premature ovarian failure
Review for gene: BRCA2 was set to GREEN
Added comment: FeRGI database- limited evidence for POI/ovarian dysgenesis- PMID:32482800,30207912- biallelic variants reported
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew edited their review of gene: BNC1: Changed publications: 32962729, 30010909, 39595984, 39462784
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew changed review comment from: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)
Sources: Literature; to: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)

New papers reported monoallelic variants in POI patients- PMID: 39595984, 39462784

Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 BNC1 Jasmine Chew gene: BNC1 was added
gene: BNC1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BNC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BNC1 were set to 32962729; 30010909
Phenotypes for gene: BNC1 were set to Premature ovarian failure 16, MIM# 618723
Review for gene: BNC1 was set to GREEN
Added comment: FeRGI database- Moderate evidence for POI- PMID:32962729,30010909 (Reported monoallelic and biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 ANKRD31 Jasmine Chew gene: ANKRD31 was added
gene: ANKRD31 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ANKRD31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD31 were set to 34794894; 34257419; 31003867
Phenotypes for gene: ANKRD31 were set to Premature ovarian failure
Review for gene: ANKRD31 was set to GREEN
Added comment: i) PMID: 34794894, PMID: 34257419- Three unrelated cases with premature ovarian failure and loss of function variants (het p.Q329∗ and c.1565-2A>G). Both mutations weakened the interaction between ANKRD31 and REC114 and were unable to further stabilise and regulate the binding of downstream DSB-forming proteins to chromatin. Mice with knocked out Ankrd31 have been reported to result in an increase in the number of DSBs and the enabling of the default DSB site, which also results in decremental efficiency of the regulation of DSB formation and may be responsible for the loss of synapsis and the delay in DSB repair (PMID: 31000436).

ii) PMID: 31003867- Unrepaired DSBs and pairing failures-stochastic on autosomes, nearly absolute on X and Y-cause meiotic arrest and sterility in males. Ankrd31-deficient females have reduced oocyte reserves. This gene plays a role in DNA double strand breaks formation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 POLR3B Jasmine Chew gene: POLR3B was added
gene: POLR3B was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3B were set to 25339210; 27512013; 26113998; 22036171; 22036172; 32319736; 26113998
Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381
Review for gene: POLR3B was set to GREEN
Added comment: Intolerome database- candidate gene for spontaneous miscarriage, FeRGI db- limited evidence for POI.

Mouse evidence-
i) PMID: 31221184-Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis. Using proteomics in a human cell line, POLR3B R103H mutation severely impairs assembly of the Pol III complex. Their mouse model indicates that the Polr3b R103H variant is embryonically lethal at or before mid-gestation, similarly to Polr3a−/−null mice , which may lead to early developmental arrest.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 PMM2 Jasmine Chew gene: PMM2 was added
gene: PMM2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 31902100; 25497157; 33583911
Phenotypes for gene: PMM2 were set to Primary ovarian failure
Review for gene: PMM2 was set to GREEN
Added comment: FeRGI db- moderate evidence for Congenital disorder of glycosylation (POI)- PMID:31902100, 25497157, 33583911(reported biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 HARS2 Jasmine Chew edited their review of gene: HARS2: Changed publications: 31449985, 21464306, 34406847
Infertility and Recurrent Pregnancy Loss v0.103 HARS2 Jasmine Chew gene: HARS2 was added
gene: HARS2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS2 were set to 31449985,21464306, 34406847
Phenotypes for gene: HARS2 were set to Perrault syndrome 2, MIM# 614926
Review for gene: HARS2 was set to GREEN
Added comment: FeRGI database- strong evidence for Perrault syndrome (POI)- PMID:31449985,21464306, 34406847(reported biallelic variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew changed review comment from: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature; to: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew changed review comment from: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with RPL, RIF, PI (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature; to: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with recurrent pregnancy loss, recurrent implantation failure and primary infertility (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GNRHR Jasmine Chew gene: GNRHR was added
gene: GNRHR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GNRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNRHR were set to 28348023; 9371856; 36385415
Phenotypes for gene: GNRHR were set to Hypogonadotropic hypogonadism 7 without anosmia, MIM#146110
Review for gene: GNRHR was set to GREEN
Added comment: Various homozygous or compound heterozygous reported by many papers (See https://omim.org/entry/138850?search=GNRHR&highlight=gnrhr#molecularGenetics)- showed phenotypic variability with varying degrees of alteration of gonadotropin function in affected members of the same family (some may be fertile while some may not).

Berkay et al. 2023 (PMID: 36385415)- Reported a case with RPL, RIF, PI (C34- het missense p.Gln106Arg with Clinvar entry- VC V000016023.12 with multiple submissions P/LP for infertility disorder or Hypogonadotropic hypogonadism, called P)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GALT Jasmine Chew changed review comment from: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289.

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature; to: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289 (Reported biallelic variants)

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 GALT Jasmine Chew gene: GALT was added
gene: GALT was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GALT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALT were set to 39440457; 19733849; 34433538; 31042289; 34730073
Phenotypes for gene: GALT were set to Premature ovarian failure
Review for gene: GALT was set to GREEN
Added comment: Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with classic galactosaemia (CG) due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. (PMID: 39440457).

FeRGI database- moderate evidence for POI- PMID:19733849, 34433538, 31042289.

Other paper:
i) PMID: 34730073- a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B4 Jasmine Chew gene: EIF2B4 was added
gene: EIF2B4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF2B4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2B4 were set to 11835386; 12707859; 14566705; 25600065; 26043506
Phenotypes for gene: EIF2B4 were set to Ovarioleukodystrophy, MIM# 620314
Review for gene: EIF2B4 was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew edited their review of gene: EIF2B5: Changed publications: 12707859, 18005052, 33245593
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew edited their review of gene: EIF2B5: Changed publications: 12707859, 18005052, 33245593.
Infertility and Recurrent Pregnancy Loss v0.103 EIF2B5 Jasmine Chew gene: EIF2B5 was added
gene: EIF2B5 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF2B5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2B5 were set to PMID:12707859; 18005052; 33245593.
Phenotypes for gene: EIF2B5 were set to Ovarioleukodystrophy, MIM# 620315
Review for gene: EIF2B5 was set to GREEN
Added comment: FeRGI database- strong evidence for POI- biallelic variants reported in PMID:12707859, 18005052,33245593.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.103 NLRP14 Zornitza Stark Classified gene: NLRP14 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.103 NLRP14 Zornitza Stark Gene: nlrp14 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Marked gene: MEI1 as ready
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.102 MEI1 Zornitza Stark Publications for gene: MEI1 were set to 30388401
Infertility and Recurrent Pregnancy Loss v0.101 MEI1 Zornitza Stark Classified gene: MEI1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.101 MEI1 Zornitza Stark Gene: mei1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Marked gene: MAJIN as ready
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Classified gene: MAJIN as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.100 MAJIN Zornitza Stark Gene: majin has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Marked gene: H6PD as ready
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Gene: h6pd has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Classified gene: H6PD as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.99 H6PD Zornitza Stark Gene: h6pd has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Marked gene: FBXO43 as ready
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Classified gene: FBXO43 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.98 FBXO43 Zornitza Stark Gene: fbxo43 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Marked gene: LARS2 as ready
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Classified gene: LARS2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.97 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Classified gene: HSD17B4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.96 HSD17B4 Zornitza Stark Gene: hsd17b4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Marked gene: FOXD1 as ready
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.95 FOXD1 Zornitza Stark Phenotypes for gene: FOXD1 were changed from to Recurrent pregnancy loss and repeated implantation failure susceptibility
Infertility and Recurrent Pregnancy Loss v0.94 FOXD1 Zornitza Stark Classified gene: FOXD1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.94 FOXD1 Zornitza Stark Gene: foxd1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Marked gene: FIGLA as ready
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Gene: figla has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Classified gene: FIGLA as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.93 FIGLA Zornitza Stark Gene: figla has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Marked gene: ESR1 as ready
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Gene: esr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Classified gene: ESR1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.92 ESR1 Zornitza Stark Gene: esr1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Marked gene: TUBA1C as ready
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.91 TUBA1C Zornitza Stark Phenotypes for gene: TUBA1C were changed from Oocyte/zygote/embryo maturation arrest to Oocyte/zygote/embryo maturation arrest 24, MIM# 621232
Infertility and Recurrent Pregnancy Loss v0.90 TUBA1C Zornitza Stark Classified gene: TUBA1C as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.90 TUBA1C Zornitza Stark Gene: tuba1c has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.89 TUBA1C Zornitza Stark reviewed gene: TUBA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Oocyte/zygote/embryo maturation arrest 24, MIM# 621232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.89 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from Oocyte/zygote/embryo maturation arrest to Oocyte/zygote/embryo maturation arrest 23, MIM# 621231
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Marked gene: TUBA4A as ready
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Gene: tuba4a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Classified gene: TUBA4A as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.88 TUBA4A Zornitza Stark Gene: tuba4a has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Marked gene: DNAAF4 as ready
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Classified gene: DNAAF4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.87 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Marked gene: CATSPER1 as ready
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Gene: catsper1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark edited their review of gene: CATSPER1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Classified gene: CATSPER1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.86 CATSPER1 Zornitza Stark Gene: catsper1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.85 CATSPER1 Zornitza Stark Tag SV/CNV tag was added to gene: CATSPER1.
Infertility and Recurrent Pregnancy Loss v0.85 CATSPER1 Zornitza Stark reviewed gene: CATSPER1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 7, MIM# 612997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.85 DNAAF1 Zornitza Stark Marked gene: DNAAF1 as ready
Infertility and Recurrent Pregnancy Loss v0.85 DNAAF1 Zornitza Stark Gene: dnaaf1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.85 DNAAF1 Zornitza Stark Classified gene: DNAAF1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.85 DNAAF1 Zornitza Stark Gene: dnaaf1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.84 STAR Zornitza Stark Marked gene: STAR as ready
Infertility and Recurrent Pregnancy Loss v0.84 STAR Zornitza Stark Gene: star has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.84 STAR Zornitza Stark Classified gene: STAR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.84 STAR Zornitza Stark Gene: star has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.83 STAR Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.83 ZFP36L2 Zornitza Stark Marked gene: ZFP36L2 as ready
Infertility and Recurrent Pregnancy Loss v0.83 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.83 ZFP36L2 Zornitza Stark Classified gene: ZFP36L2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.83 ZFP36L2 Zornitza Stark Gene: zfp36l2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.82 FIGLA Jasmine Chew gene: FIGLA was added
gene: FIGLA was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FIGLA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FIGLA were set to 18499083; 29914564; 30474133; 34778283
Phenotypes for gene: FIGLA were set to Premature ovarian failure 6, MIM# 612310
Review for gene: FIGLA was set to GREEN
Added comment: Literature in OMIM- PubMed:18499083; 29914564; 30474133

New paper:
i) PMID: 34778283- Three different FIGLA heterozygous variants were identified in four patients with POI. Two patients carried the mutation c.11C>A (p.A4E), and the other two patients, respectively, carried the mutations c.625G>A (p.V209I) and c.84C>A (p.D28E). The luciferase reporter assay indicated that ZP1, ZP2, and ZP3 transcriptional activities were significantly reduced in individuals with FIGLA mutations. Chromatin immunoprecipitation indicated that the FIGLA mutation significantly decreased binding with the ZP1, ZP2, and ZP3 promoters.

Documented in FeRGI database- strong evidence for POI.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 NR5A1 Jasmine Chew edited their review of gene: NR5A1: Changed publications: 20887963, 19246354, 23918653, 31513305
Infertility and Recurrent Pregnancy Loss v0.82 NR5A1 Jasmine Chew edited their review of gene: NR5A1: Added comment: New review paper on variants associated with male and female infertility- PMID: 31513305

Documented in FeRGI database- moderate/definitive evidence for POI.; Changed publications: 20887963, 19246354, 23918653
Infertility and Recurrent Pregnancy Loss v0.82 NR5A1 Jasmine Chew Deleted their comment
Infertility and Recurrent Pregnancy Loss v0.82 NR0B1 Jasmine Chew gene: NR0B1 was added
gene: NR0B1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NR0B1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NR0B1 were set to 12519885; 23384712; 26207377
Phenotypes for gene: NR0B1 were set to Congenital adrenal hypoplasia, #MIM 300200
Review for gene: NR0B1 was set to GREEN
Added comment: Absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients.
- Literature in OMIM: PubMed: 12519885; 23384712; 26207377
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 POLG Jasmine Chew gene: POLG was added
gene: POLG was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POLG was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLG were set to 29992832; 16595552; 22405928; 20701905
Phenotypes for gene: POLG were set to Premature ovarian failure
Review for gene: POLG was set to GREEN
Added comment: POLG-related disorders and mitochondrial diseases
i) PMID: 29992832: Identified the first homozygous POLG variant (p.R964C) in a female with ovarian dysfunction and complete fertilization failure undergoing ICSI; previous papers have reported various heterozygous variants in association with POI/POF.

ii) PMID: 16595552- heterozygous p.Y955C and p.R943H variants reported in unrelated patients with premature ovarian failure.

iii) PMID: 22405928- heterozygous p.Y951N mutation in POLG was found in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis (a severe form of POF) and 3-methylglutaconic aciduria.

iv) PMID: 20701905- heterozygous p.R953C variant in a female with spontaneous POI.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 NR5A1 Jasmine Chew gene: NR5A1 was added
gene: NR5A1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NR5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR5A1 were set to 20887963; 19246354; 37409232
Phenotypes for gene: NR5A1 were set to Premature ovarian failure 7, MIM #612964; Spermatogenic failure 8, # 613957
Review for gene: NR5A1 was set to GREEN
Added comment: New paper:
i) PMID: 37409232- Novel heterozygous frameshift variant p.(Phe70Serfs*5) in a patient with with a disorder of sex development and arrest of spermatogenesis at the spermatocyte stage.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 MSH5 Jasmine Chew edited their review of gene: MSH5: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.82 MSH5 Jasmine Chew gene: MSH5 was added
gene: MSH5 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH5 were set to 28175301; 18166824; 34755185
Phenotypes for gene: MSH5 were set to Premature ovarian failure 13, MIM #617442; Spermatogenic failure 74, MIM# 619937
Added comment: Literature in OMIM- PubMed: 28175301;18166824;34755185

New paper:
i) PMID: 36793102 (2023)- digenic het variants in MSH4 and MSH5 (first report indicating that not only one subunit deficiency, but also dysfunctional MSH4-MSH5 interaction or cumulative haploinsufficiency of both subunits, may disrupt homologous recombination during meiosis, finally causing POI).

Documented in FeRGI database- moderate evidence for POI.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 LMNA Jasmine Chew gene: LMNA was added
gene: LMNA was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LMNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNA were set to 18364375; 19283854; 39595984
Phenotypes for gene: LMNA were set to Female infertility, premature ovarian insufficiency
Review for gene: LMNA was set to GREEN
Added comment: Variants reported associated with female infertility and POI:
i) PMID: 18364375- seven families with 14 affected patients exhibiting heterozygous LMNA variants (five R482W, one R482Q, one R439C) and 7 percent of LMNA-mutated women exhibited a clinical phenotype of PCOS, 4 suffered from infertility, and 7 experienced at least one miscarriage, also quoted that "The prevalence of PCOS, infertility, miscarriages, gestational diabetes, and/or macrosomia and eclampsia or fetal death was much higher in LMNA-mutated women than in the general population (20–27)"

ii) PMID: 19283854- novel heterozygous missense pLeu59Arg in two unrelated patients with cardinal features of Malouf syndrome, that is, dilated cardiomyopathy and premature ovarian failure

iii) PMID: 39595984- Six different P/LP heterozygous variants in six unrelated patients with apparently isolated diminished ovarian reserve.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 LHB Jasmine Chew gene: LHB was added
gene: LHB was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LHB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LHB were set to 1727547; 12189497; 19126631; 17761593; 19890128; 15569941; 39786527; 35470463
Phenotypes for gene: LHB were set to Hypogonadotropic hypogonadism 23 with or without anosmia, MIM# 228300
Review for gene: LHB was set to GREEN
Added comment: Literature in OMIM- PubMed: 1727547;12189497; 19126631; 17761593; 19890128; 15569941

New papers:
i) PMID: 39786527- compound heterozygous variants in a female patient with congenital hypogonadotropic hypogonadism (CHH) and functional study revealed higher intracellular LH concentrations and lower extracellular LH concentrations compared to the wild type indicate secretion dysfunction for LH

ii) PMID: 35470463- a novel homozygous missense p.Cys46Arg in an Indian male with infertility
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 LARS2 Jasmine Chew gene: LARS2 was added
gene: LARS2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS2 were set to 23541342; 26657938; 30737337; 32442335
Phenotypes for gene: LARS2 were set to Perrault syndrome 4, MIM# 615300
Review for gene: LARS2 was set to GREEN
Added comment: Premature ovarian failure (POF) in females
- Literature in OMIM- PubMed: 23541342, 26657938, 30737337, 32442335

Documented in FeRGI database- strong evidence for POI.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 FOXD1 Jasmine Chew edited their review of gene: FOXD1: Changed phenotypes: Recurrent pregnancy loss and repeated implantation failure susceptibility
Infertility and Recurrent Pregnancy Loss v0.82 FOXD1 Jasmine Chew gene: FOXD1 was added
gene: FOXD1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FOXD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXD1 were set to 27805902; 31395028
Review for gene: FOXD1 was set to GREEN
Added comment: i) PMID: 27805902- 18 heterozygous (only 10 were nonsynonymous) variants were identified only in recurrent spontaneous abortion (RSA) patients (total of 33 patients) not seen in ctrl group, and only 3 variants had functional assays performed- p.Ala356Gly (x1 patient),p.Ile364Met (x2 patients), and p.Ins429AlaAla (x12 patients). In vitro assays revealed they had a functional effect as they led to perturbations in FOXD1 transactivation properties on promoters of the Placental Growth Factor (PGF) and the complement component gene (C3) having key roles during implantation/placentation.

ii) PMID: 31395028- 9 heterozygous non-synonymous variants in patients affected by PE, IUGR, RPL and repeated implantation failure (RIF) , two of which (p.His267Tyr found in one RIF patient and p.Arg57del in one IUGR woman) represented novel and coherent candidates for in vitro testing. Functional experiments revealed that both led to an increased C3 (complement C3) promoter transcriptional activity. Also found increased FOXD1-p.Arg57del variant transactivation capacity on the PlGF (placental growth factor) promoter.The FOXD1 p.Ala356Gly and p.Ile364Met variants (previously found in RPL patients in PMID: 27805902) have also been identified in the present work in women with PE and IUGR and with isolated IUGR, respectively.

Documented in FeRGI database- limited evidence for repeated implantation failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 SPEF2 Jasmine Chew gene: SPEF2 was added
gene: SPEF2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344; 39753944; 38568462
Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM# 618751
Review for gene: SPEF2 was set to GREEN
Added comment: Literature in OMIM- PubMed: 31151990, 31278745, 31048344

New papers
i) PMID: 39753944 - two patients with MMAF carrying novel biallelic variants (homozygous p.Glu715Ter and com het p.Arg1123Gln/p.Ile193Thr). Functional analysis of two novel missense variants of SPEF2 demonstrated a mild impact on morphological extension in a transfected cell model. These cells exhibited alterations in cell diameter, likely reflecting impaired cargo protein transport due to SPEF2 mutations, thereby affecting cell growth and extension.

ii) PMID: 38568462 -four novel SPEF2 variants, including one novel homozygous splicing site variant c.4447 + 1G > A, novel compound heterozygous nonsense variants p.R447* and p.E549* and one novel homozygous missense variant p.D842N. All variants were present at very low levels in public databases, predicted to be deleterious in silico prediction tools, and were further confirmed deleterious by in vitro analyses. Ultrastructural analyses of the spermatozoa of the patients revealed the absence of the central pair complex in the sperm flagella.

Intolerome database- candidate gene for spontaneous miscarriage
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 DNAAF1 Jasmine Chew gene: DNAAF1 was added
gene: DNAAF1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAAF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAAF1 were set to 19944400; 19944405; 33174003
Phenotypes for gene: DNAAF1 were set to Primary ciliary dyskinesia 13, #MIM 613193
Review for gene: DNAAF1 was set to GREEN
Added comment: Literature in OMIM: PMID:19944400;19944405

New paper:
PMID: 33174003- biallelic variants in two patients (P1- com het p.Met1Ile,.124+1G>C, and p.Glu126Lysfs*35 and P2- hom p.Lys315*) with primary ciliary dyskinesia and infertility.

Documented in FeRGI database- limited evidence for reduced fertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 IKBKG Jasmine Chew gene: IKBKG was added
gene: IKBKG was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: IKBKG was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: IKBKG were set to Incontinentia pigmenti, MIM# 308300
Review for gene: IKBKG was set to GREEN
Added comment: Intolerome database- Known for male lethal. First trimester miscarriage.

Gene Review- Women with IP are at increased risk for pregnancy loss, presumably related to low viability of male fetuses. It is common for women with IP to experience multiple miscarriages, often around the third or fourth month of gestation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 HSD17B4 Jasmine Chew changed review comment from: Characterized by ovarian dysgenesis in females
- Literature in OMIM: PubMed: 20673864

New paper reported ovarian dysgenesis phenotype
i) PMID: 28830375- novel homozygous variant p.A100S in two female siblings
Sources: Literature; to: Characterized by ovarian dysgenesis in females
- Literature in OMIM: PubMed: 20673864

New paper reported ovarian dysgenesis phenotype
i) PMID: 28830375- novel homozygous variant p.A100S in two female siblings

Documented in FeRGI database- moderate evidence for POI.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 HSD17B4 Jasmine Chew gene: HSD17B4 was added
gene: HSD17B4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HSD17B4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSD17B4 were set to 20673864; 28830375
Phenotypes for gene: HSD17B4 were set to Perrault syndrome 1, #MIM 233400
Review for gene: HSD17B4 was set to GREEN
Added comment: Characterized by ovarian dysgenesis in females
- Literature in OMIM: PubMed: 20673864

New paper reported ovarian dysgenesis phenotype
i) PMID: 28830375- novel homozygous variant p.A100S in two female siblings
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 H6PD Jasmine Chew commented on gene: H6PD: Literature in OMIM: PMID: 12858176, 18628520, 18628520
- Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility.

PMID: 36385415- Reported a case with RPL (C22), carrying heterozygous frameshift p.Ser391AlafsTer102 called pathogenic, absent from Clinvar
Infertility and Recurrent Pregnancy Loss v0.82 H6PD Jasmine Chew Deleted their comment
Infertility and Recurrent Pregnancy Loss v0.82 H6PD Jasmine Chew gene: H6PD was added
gene: H6PD was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: H6PD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: H6PD were set to 12858176; 18628520; 18628520; 36385415
Phenotypes for gene: H6PD were set to Cortisone reductase deficiency 1, MIM# 604931
Review for gene: H6PD was set to GREEN
Added comment: Literature in OMIM: PMID: 12858176, 18628520, 18628520
- Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility.

PMID: 36385415- Reported a case with RPL (C22), carrying heterozygous frameshift p.Ser391AlafsTer102 called pathogenic, absent from Clinvar
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 GNRH1 Jasmine Chew gene: GNRH1 was added
gene: GNRH1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GNRH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNRH1 were set to 19535795; 19567835; 32134721; 31200363; 26595427; 34923491
Phenotypes for gene: GNRH1 were set to Hypogonadotropic hypogonadism 12 with or without anosmia, MIM# 614841
Review for gene: GNRH1 was set to GREEN
Added comment: New paper:
i) PMID: 34923491- Two male probands with reproductive phenotypes (but not sterile) in their Indian cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A>G); also reviewed previously reported cases with GNRH1 variants suggests GNRH1 biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 FGF8 Jasmine Chew gene: FGF8 was added
gene: FGF8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FGF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF8 were set to 20463092; 18596921
Phenotypes for gene: FGF8 were set to Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702
Review for gene: FGF8 was set to GREEN
Added comment: Characterized by absent or incomplete sexual maturation (Females an be presented with Primary amenorrhea).
Literature in OMIM- PMID: 20463092, 18596921

Documented in FeRGI database- moderate evidence for Hypogonadotropic hypogonadism (HH).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 ESR1 Jasmine Chew gene: ESR1 was added
gene: ESR1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ESR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESR1 were set to 8090165; 23841731; 27754803
Phenotypes for gene: ESR1 were set to Estrogen resistance, MIM# 615363
Review for gene: ESR1 was set to GREEN
Added comment: Literature in OMIM- PMID: 8090165; 23841731; 27754803
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 EIF2B2 Jasmine Chew gene: EIF2B2 was added
gene: EIF2B2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2B2 were set to 12707859; 21484434
Phenotypes for gene: EIF2B2 were set to Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure, MIM# 603896
Review for gene: EIF2B2 was set to GREEN
Added comment: Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 CDC25A Jasmine Chew gene: CDC25A was added
gene: CDC25A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CDC25A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC25A were set to 40342881; 30009144; 16720623
Phenotypes for gene: CDC25A were set to Spermatogenic failure
Review for gene: CDC25A was set to GREEN
Added comment: i) PMID: 40342881- Five novel heterozygous variants (Lys500Asn in 8 cases, His459Leu in 12 cases, Ser485Asp, Thr503Ser, c.1434 + 5G>C) and one previously identified SNP (in 7 cases) in azoospermic males from the Bengali-speaking Indian population. qPCR analysis indicated downregulation of CDC25A mRNA expression in azoospermic patients relative to fertile controls. Relative expression levels of CDC25A were about 2.5-fold lower in azoospermic testicular tissue and semen samples, reflecting diminished transcriptional activity in affected patients. This reduction in gene expression may reflect a potential functional deficiency of CDC25A, contributing to spermatogenic arrest. The decreased level of CDC25A mRNA levels corresponds with the findings of pathogenic variants identified in azoospermic patients, thus solidifying the evidence of CDC25A mutations contributing to male infertility.

ii) PMID: 30009144,16720623- decreased expression of CDC25A observed in testicular biopsies from azoospermic men, suggesting association with meiotic arrest as the etiology of spermatogenic failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 CATSPER1 Jasmine Chew gene: CATSPER1 was added
gene: CATSPER1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CATSPER1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CATSPER1 were set to 19344877; 11595941
Phenotypes for gene: CATSPER1 were set to Spermatogenic failure 7, MIM# 612997
Review for gene: CATSPER1 was set to GREEN
Added comment: Literature in OMIM- PMID:19344877;11595941
- Homozygous Lys180LysfsTer8 (2 brother) and Asp317MetfsTer18 (unrelated male) in 3 infertile males from 2 consanguineous Iranian families. Both were truncating variants.CatSper1−/− mouse sperm were sluggish, showed less directed movement and exhibited impaired track speed, path velocity and progressive velocity.21 This markedly reduced motility was shown to eliminate the ability of CatSper-null sperm to fertilize oocytes in vitro.

No new cases reported so far.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 BCORL1 Jasmine Chew changed review comment from: i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.

Byrne et al. 2023- male fetus terminated at 22+3 GA due to abnormal renal morphology, Cleft upper lip, Median cleft palate, Ovotestis, enlarged hyroid, oral frenulae carrying hemizygous p.Tyr1692Ter called VUS- novel phenotype
Sources: Literature; to: i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.

Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 BCORL1 Jasmine Chew gene: BCORL1 was added
gene: BCORL1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BCORL1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BCORL1 were set to 38342987; 32376790; 39267058; 39189935
Phenotypes for gene: BCORL1 were set to Spermatogenic failure
Review for gene: BCORL1 was set to GREEN
Added comment: i) PMID: 38342987- novel hemizygous nonsense variant (c.1564G > T:p.Glu522*) in a male patient with oligoasthenoteratozoospermia (OAT) from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Also identified four hemizygous missense variants (c.2615T > G:p.Val872Gly, c.2669G > A:p.Arg890Gln, c.3164A > G:p.Asp1055Gly and c.3344C > T:p.Pro1115Leu) in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%). They hypothesized that the BCORL1 (c.2615 T > G, c.2669G > A, c.3164A > G, c.3344C > T) missense mutations may have led to an accumulation of dysfunctional toxic proteins that resulted in a more severe male infertility phenotype in the patient (NOA).

ii) PMID: 32376790- Hemizygous missense variant in a male patient with NOA without other diseases, which also found that the knockout of Bcorl1 in mice resulted in OAT with the abnormal brain development. It had not been previously linked to male infertility. This study demonstrates, for the first time, that loss of Bcorl1 causes spermatogenesis failure.

iii) PMID: 39267058- hemizygous missense variant (p.Arg19Gln) in a infertile male with oliogasthenozoospermia, no functional data

iv) PMID: 39189935- novel hemizygous missense variant (p.G1391R) and a recurrent variant (p.V872G) in BCORL1 from four OAT patients. Functional assays showed that the variants disturb the transcription of spermatogenetic genes such as SYCE1 and DAZL, impair the interaction with HDAC7, and cause epigenetic changes such as changes in level of histone modification with different extent, including the enhancement in acetylation of H3K14, and the reduction in acetylation of H4K5 and H4K8.

Byrne et al. 2023- male fetus terminated at 22+3 GA due to abnormal renal morphology, Cleft upper lip, Median cleft palate, Ovotestis, enlarged hyroid, oral frenulae carrying hemizygous p.Tyr1692Ter called VUS- novel phenotype
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.82 DNAH12 Zornitza Stark Marked gene: DNAH12 as ready
Infertility and Recurrent Pregnancy Loss v0.82 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.82 DNAH12 Zornitza Stark Classified gene: DNAH12 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.82 DNAH12 Zornitza Stark Gene: dnah12 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.81 DNAH12 Zornitza Stark gene: DNAH12 was added
gene: DNAH12 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH12 were set to 39071892; 40146200
Phenotypes for gene: DNAH12 were set to Spermatogenic failure 100, MIM# 621209
Review for gene: DNAH12 was set to GREEN
Added comment: Twelve individuals from 7 families and two mouse models support this association.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.80 NLRP14 Jasmine Chew gene: NLRP14 was added
gene: NLRP14 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NLRP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP14 were set to 38060382
Phenotypes for gene: NLRP14 were set to Oocyte maturation defect and early embryo arrest
Review for gene: NLRP14 was set to AMBER
Added comment: PMID: 38060382- Compound heterozygous variants (p.Cys428Profs∗28/p.Leu887delinsArgTyr) reported in an infertile woman with oocyte maturation defects and early embryo arrest (EEA).
- Functional analysis showed comparable protein levels compared with the wild-type control, although a truncated band of the expected size (47 kDa) was observed for the p.Cys428Profs∗28 variant.
-The truncated variant, p.Cys428Profs∗28, is lacking the LRR domain and, hence, completely loses the ability to bind with UHRF1. The p.Leu887delinsArgTyr variant results in significant alteration in binding modes with decreased binding area and binding free energy, which introduced regional instability in the NLRP14-UHRF1 interaction. The interaction of both variants and UHRF1 was disrupted and might lead to increased UHRF1 protein degradation in oocytes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.80 OOEP Jasmine Chew edited their review of gene: OOEP: Changed phenotypes: Recurrent preimplantation embryonic arrest, Female infertility due to oocyte meiotic arrest, MONDO:0044626
Infertility and Recurrent Pregnancy Loss v0.80 OOEP Jasmine Chew gene: OOEP was added
gene: OOEP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: OOEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OOEP were set to 35946397
Phenotypes for gene: OOEP were set to Recurrent preimplantation embryonic arrest
Review for gene: OOEP was set to AMBER
Added comment: i) PMID: 35946397- Compound heterozygous missense variants (p.Arg37Gly and p.Arg37Pro) identified in a patient who experienced recurrent preimplantation embryonic arrest.
- Immunofluorescence and western blot analysis showed that both variants lead to reduced OOEP protein expression compared with that in the wild type.
- Transcriptomic analysis showed that mutant OOEP‐affected embryos had downregulation of gene transcripts, indicating that substantial number of mRNAs were not transcribed or were decayed in the affected embryo. The GO analysis results revealed that these downregulated genes were mainly enriched in protein binding, translation, mRNA processing, and mitochondrial function.

ii) PMID: 39379527- showed functionally that the two reported variants result in significantly destabilizing intercomponent interactions among the subcortical maternal complex (SCMC) subunits.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.80 PANX1 Zornitza Stark Marked gene: PANX1 as ready
Infertility and Recurrent Pregnancy Loss v0.80 PANX1 Zornitza Stark Gene: panx1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.80 PANX1 Zornitza Stark Classified gene: PANX1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.80 PANX1 Zornitza Stark Gene: panx1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.79 SEPT4 Zornitza Stark Marked gene: SEPT4 as ready
Infertility and Recurrent Pregnancy Loss v0.79 SEPT4 Zornitza Stark Gene: sept4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.79 SEPT4 Zornitza Stark Classified gene: SEPT4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.79 SEPT4 Zornitza Stark Gene: sept4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.78 SEPT4 Zornitza Stark gene: SEPT4 was added
gene: SEPT4 was added to Infertility and Pregnancy Loss. Sources: Expert Review
Mode of inheritance for gene: SEPT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEPT4 were set to 36135717; 15737931; 15737930
Phenotypes for gene: SEPT4 were set to Spermatogenic failure 99, MIM# 621194
Review for gene: SEPT4 was set to GREEN
Added comment: Two unrelated cases with primary male infertility (asthenoteratozoospermia) from consanguineous Chinsese families with 2 difference homozygous stopgain variants (Patient 1: c.721A>T, p.R241* and Patient 2: c.205C>T, p.R69*). Multiple supporting mouse models where the male mice are sterile.
Sources: Expert Review
Infertility and Recurrent Pregnancy Loss v0.77 TUBA1C Jasmine Chew gene: TUBA1C was added
gene: TUBA1C was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TUBA1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBA1C were set to 39209701
Phenotypes for gene: TUBA1C were set to Oocyte/zygote/embryo maturation arrest
Review for gene: TUBA1C was set to GREEN
Added comment: New paper (biallelic variants for OZEMA)-
i) PMID: 39209701- patients 1 and 2 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carrying homozygous nonsense variant (p.Gln358Ter) and frameshift deletion variant (p.Tyr444Metfs*42), respectively. Transfection studies showed that both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 TUBA4A Jasmine Chew edited their review of gene: TUBA4A: Changed publications: 39209701, 37024973, 39872894
Infertility and Recurrent Pregnancy Loss v0.77 TUBA4A Jasmine Chew changed review comment from: New papers reporting biallelic and monoallelic variants associated with OZEMA:
i) PMID: 39209701- patients 3 and 4 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carried homozygous frameshift deletion variant c.1319_1320del (p.Tyr440Ter) and missense variant c.1015C>T (p.Arg339Cys) of TUBA4A, respectively. Transfection studies showed that caused both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation. Differentially abundant transcripts in arrested embryos carrying the missense TUBA4A variant exhibited a trend of upregulation and were highly enriched in the mRNA metabolic process, and some key genes involved in degradation, such as MOS and PABPN1L have been shown to be significantly downregulated.

ii) PMID: 37024973 - reported three unrelated infertile females with similar phenotypes of embryonic arrest carrying different de novo heterozygous missense variants (pE77K, pL286P, p.C347K). Functional study showed that all the three mutant proteins caused severe microtubule destabilization. They also identified additional nine sporadic cases (seven were with phenotype of early embryonic arrest and two with phenotype of oocyte maturation arrest) with eight different heterozygous missense TUBA4A variants. Functional study showed that six out of the eight variants (R215H, R229C, A273V, E284K, A314V, and R373H) were incorporated in microtubules with a more severely abnormal appearance. Microinjection of TUBA4A mutant cRNAs (8 out of 11 variants) significantly reduced the rate of first polar body extrusion to 24.5–66.3% and microinjection of TUBA4A mutant cRNAs (6 out of 11 variants) also resulted in embryonic development arrest and reduced the rate of blastocyst formation to 51.0–65.0%.

iii) PMID: 39872894- Three isolated infertile female with zygotic arrest carrying heterozygous missense variants (P1- de novo p.E284K, P2- p.E284G, P3- p.E284K). Injection of mRNA encoding E284G and E284K mutants into mouse GV oocytes showed highly disrupted spindle morphology and apparent chromosome misalignment, only about 30% E284G- and E284K-injected oocytes completed meiosis I.
Sources: Literature; to: New papers reporting biallelic and monoallelic variants associated with OZEMA:
i) PMID: 39209701- Patients 3 and 4 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carried homozygous frameshift deletion variant p.Tyr440Ter and missense variant p.Arg339Cys respectively. Transfection studies showed that caused both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation. Differentially abundant transcripts in arrested embryos carrying the missense TUBA4A variant exhibited a trend of upregulation and were highly enriched in the mRNA metabolic process, and some key genes involved in degradation, such as MOS and PABPN1L have been shown to be significantly downregulated.

ii) PMID: 37024973 - Three unrelated infertile females with similar phenotypes of embryonic arrest carrying different de novo heterozygous missense variants (pE77K, pL286P, p.C347K). Functional study showed that all the three mutant proteins caused severe microtubule destabilization. They also identified additional nine sporadic cases (seven were with phenotype of early embryonic arrest and two with phenotype of oocyte maturation arrest) with eight different heterozygous missense TUBA4A variants. Functional study showed that six out of the eight variants (R215H, R229C, A273V, E284K, A314V, and R373H) were incorporated in microtubules with a more severely abnormal appearance. Microinjection of TUBA4A mutant cRNAs (8 out of 11 variants) significantly reduced the rate of first polar body extrusion to 24.5–66.3% and microinjection of TUBA4A mutant cRNAs (6 out of 11 variants) also resulted in embryonic development arrest and reduced the rate of blastocyst formation to 51.0–65.0%.

iii) PMID: 39872894- Three isolated infertile female with zygotic arrest carrying heterozygous missense variants (P1- de novo p.E284K, P2- p.E284G, P3- p.E284K). Injection of mRNA encoding E284G and E284K mutants into mouse GV oocytes showed highly disrupted spindle morphology and apparent chromosome misalignment, only about 30% E284G- and E284K-injected oocytes completed meiosis I.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 TUBA4A Jasmine Chew edited their review of gene: TUBA4A: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.77 TUBA4A Jasmine Chew gene: TUBA4A was added
gene: TUBA4A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TUBA4A were set to 39209701; 37024973; 37024973
Phenotypes for gene: TUBA4A were set to Oocyte/zygote/embryo maturation arrest
Added comment: New papers reporting biallelic and monoallelic variants associated with OZEMA:
i) PMID: 39209701- patients 3 and 4 from unrelated families with primary infertility experiencing recurrent preimplantation embryo development arrest (RPEA) carried homozygous frameshift deletion variant c.1319_1320del (p.Tyr440Ter) and missense variant c.1015C>T (p.Arg339Cys) of TUBA4A, respectively. Transfection studies showed that caused both variants caused a significant decrease in the abundance of encoded proteins and abnormal cytoplasmic localisation manifested as localised protein aggregation. Differentially abundant transcripts in arrested embryos carrying the missense TUBA4A variant exhibited a trend of upregulation and were highly enriched in the mRNA metabolic process, and some key genes involved in degradation, such as MOS and PABPN1L have been shown to be significantly downregulated.

ii) PMID: 37024973 - reported three unrelated infertile females with similar phenotypes of embryonic arrest carrying different de novo heterozygous missense variants (pE77K, pL286P, p.C347K). Functional study showed that all the three mutant proteins caused severe microtubule destabilization. They also identified additional nine sporadic cases (seven were with phenotype of early embryonic arrest and two with phenotype of oocyte maturation arrest) with eight different heterozygous missense TUBA4A variants. Functional study showed that six out of the eight variants (R215H, R229C, A273V, E284K, A314V, and R373H) were incorporated in microtubules with a more severely abnormal appearance. Microinjection of TUBA4A mutant cRNAs (8 out of 11 variants) significantly reduced the rate of first polar body extrusion to 24.5–66.3% and microinjection of TUBA4A mutant cRNAs (6 out of 11 variants) also resulted in embryonic development arrest and reduced the rate of blastocyst formation to 51.0–65.0%.

iii) PMID: 39872894- Three isolated infertile female with zygotic arrest carrying heterozygous missense variants (P1- de novo p.E284K, P2- p.E284G, P3- p.E284K). Injection of mRNA encoding E284G and E284K mutants into mouse GV oocytes showed highly disrupted spindle morphology and apparent chromosome misalignment, only about 30% E284G- and E284K-injected oocytes completed meiosis I.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 MEIOB Jasmine Chew gene: MEIOB was added
gene: MEIOB was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MEIOB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MEIOB were set to 28206990; 34392356; 35991565; 37715646; 31000419; 39545410; 30838384
Phenotypes for gene: MEIOB were set to Premature ovarian failure 23, MIM# 620686; Spermatogenic failure 22, MIM# 617706
Review for gene: MEIOB was set to GREEN
Added comment: Literature in OMIM- PMID: 28206990; 34392356; 35991565; 37715646; 31000419- multiple unrelated infertile males due to spermatogenic failure and females due to premature ovarian failure carrying biallelic variants, supported by functional evidence.

New papers:
i) PMID: 39545410- previously reported homozygous nonsense p.(Arg272*) in proband 2136 (Egyptian), with a history of 6 early miscarriages, 3 failed intracytoplasmic sperm injection cycles, 1 HM, and low anti-Müllerian hormone (AMH) (2 times ≤0.2 ng/mL).

ii) PMID: 30838384- A novel homozygous frameshift variant in two brothers of Arab ethnicity. This frame-shift is predicted to result in a truncated MEIOB protein, which lacks the conserved C-terminal DNA binding domain.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 SYCP2 Jasmine Chew changed review comment from: Literature in OMIM- PMID: 31866047- Three men with oligo- or azoospermia with heterozygous truncating variants.

New papers (monoallelic and biallelic variants for male infertility):
i) PMID: 39202451- Novel heterozygous loss-of-function (LOF) variants (c.89dup, c.946_947del, and c.4378_4379del) reported in three unrelated Chinese patients with oligoasthenozoospermia.

ii) PMID: 38511217- Heterozygous p.I63S and p.R509del in two unrelated NOA-affected males (Case 10 and 11).

iii) PMID: 37337432- Homozygous loss-of-function variant (c.2689_2690insT) in an NOA-affected patient. HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA.

New paper (biallelic variant for Hydatidiform mole):
i) PMID: 39545410- A homozygous splice variant at acceptor site c.2530-2A>G in patient 1954 (Egyptian), with 4 CHMs and 2 years of primary and secondary infertility (before the first and after the third HM). In silico analysis of the effect of this variant on SYCP2 splicing using Human Splicing Finder (21) predicted that the c.2530-2A>G variant abolishes the splice acceptor site of exon 27 and impairs normal splicing. SYCP2 codes for an axial/lateral element of the synaptonemal complex that is essential for meiotic homologous chromosome synapsis. Male Sycp2-null mice are infertile, while the females have reduced litter sizes (PMID: 16717126). In humans, SYCP2 P/LP variants have been reported in a heterozygous state in infertile males but not in women with reproductive failure.
Sources: Literature; to: Literature in OMIM- PMID: 31866047- Three men with oligo- or azoospermia with heterozygous truncating variants.

New papers (monoallelic and biallelic variants for male infertility):
i) PMID: 39202451- Novel heterozygous loss-of-function (LOF) variants (c.89dup, c.946_947del, and c.4378_4379del) reported in three unrelated Chinese patients with oligoasthenozoospermia.

ii) PMID: 38511217- Heterozygous p.I63S and p.R509del in two unrelated NOA-affected males (Case 10 and 11).

iii) PMID: 37337432- Homozygous loss-of-function variant (c.2689_2690insT) in an NOA-affected patient. HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA.

New paper (biallelic variant for hydatidiform mole):
i) PMID: 39545410- A homozygous splice variant at acceptor site c.2530-2A>G in patient 1954 (Egyptian), with 4 CHMs and 2 years of primary and secondary infertility (before the first and after the third HM). In silico analysis of the effect of this variant on SYCP2 splicing using Human Splicing Finder (21) predicted that the c.2530-2A>G variant abolishes the splice acceptor site of exon 27 and impairs normal splicing. SYCP2 codes for an axial/lateral element of the synaptonemal complex that is essential for meiotic homologous chromosome synapsis. Male Sycp2-null mice are infertile, while the females have reduced litter sizes (PMID: 16717126). In humans, SYCP2 P/LP variants have been reported in a heterozygous state in infertile males but not in women with reproductive failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 SYCP2 Jasmine Chew gene: SYCP2 was added
gene: SYCP2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SYCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2 were set to 31866047; 39202451; 38511217; 37337432; 39545410
Phenotypes for gene: SYCP2 were set to Spermatogenic failure 1, MIM# 258150; Hydatidiform mole
Review for gene: SYCP2 was set to GREEN
Added comment: Literature in OMIM- PMID: 31866047- Three men with oligo- or azoospermia with heterozygous truncating variants.

New papers (monoallelic and biallelic variants for male infertility):
i) PMID: 39202451- Novel heterozygous loss-of-function (LOF) variants (c.89dup, c.946_947del, and c.4378_4379del) reported in three unrelated Chinese patients with oligoasthenozoospermia.

ii) PMID: 38511217- Heterozygous p.I63S and p.R509del in two unrelated NOA-affected males (Case 10 and 11).

iii) PMID: 37337432- Homozygous loss-of-function variant (c.2689_2690insT) in an NOA-affected patient. HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA.

New paper (biallelic variant for Hydatidiform mole):
i) PMID: 39545410- A homozygous splice variant at acceptor site c.2530-2A>G in patient 1954 (Egyptian), with 4 CHMs and 2 years of primary and secondary infertility (before the first and after the third HM). In silico analysis of the effect of this variant on SYCP2 splicing using Human Splicing Finder (21) predicted that the c.2530-2A>G variant abolishes the splice acceptor site of exon 27 and impairs normal splicing. SYCP2 codes for an axial/lateral element of the synaptonemal complex that is essential for meiotic homologous chromosome synapsis. Male Sycp2-null mice are infertile, while the females have reduced litter sizes (PMID: 16717126). In humans, SYCP2 P/LP variants have been reported in a heterozygous state in infertile males but not in women with reproductive failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 CCDC155 Jasmine Chew changed review comment from: Note- HGNC Approved Gene Symbol: KASH5 (MIM #618125)

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410-compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature; to: Note- HGNC Approved Gene Symbol: KASH5 (MIM #618125)

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410- Compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 CCDC155 Jasmine Chew changed review comment from: Note- HGNC Approved Gene Symbol: KASH5

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410-compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature; to: Note- HGNC Approved Gene Symbol: KASH5 (MIM #618125)

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410-compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 CCDC155 Jasmine Chew gene: CCDC155 was added
gene: CCDC155 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC155 were set to 29790874; 35674372; 36864840; 35708642; 39545410
Phenotypes for gene: CCDC155 were set to Premature ovarian failure 22, MIM# 620548; Spermatogenic failure 88, MIM# 620547
Review for gene: CCDC155 was set to GREEN
Added comment: Note- HGNC Approved Gene Symbol: KASH5

Literature in OMIM- PMID: 29790874; 35674372; 36864840;35708642- multiple unrelated infertile females (diminished ovarian reserve, recurrent miscarriage) and males (NOA) with different biallelic variants

New paper:
i) PMID: 39545410-compound heterozygous variants pArg519* and p.Leu535Gln in patient 439 (Jordanian), with 3 HMs and 2 miscarriages. The L535Q variant was previously reported in a homozygous state by Fakhro et al. in 2 infertile Qatari brothers with azoospermia (PMID: 29790874). In mice, both male and female null mutants of Kash5 are infertile (PMID: 24062341).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 C11orf80 Jasmine Chew edited their review of gene: C11orf80: Changed publications: 30388401, 36732965
Infertility and Recurrent Pregnancy Loss v0.77 MAJIN Jasmine Chew gene: MAJIN was added
gene: MAJIN was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MAJIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAJIN were set to 39545410; 33211200
Phenotypes for gene: MAJIN were set to Recurrent hydatidiform mole, non-obstructive azoospermia
Review for gene: MAJIN was set to AMBER
Added comment: New papers (biallelic variant for HM/male infertility):
i) PMID: 39545410- Novel homozygous splice donor site variant c.349+1G>T in patient 1824 (Italian) with 2 HMs followed by secondary infertility and substantially reduced bilateral ovarian volumes. MAJIN codes for a junction protein that forms a complex with TERB1 and TERB2, which together bind to telomeres and anchor them to the inner nuclear membrane components KASH5 and SUN1. This attachment of chromosomes to the nuclear envelope is essential for homologous chromosome movement and synapsis. In mice, both male and female null mutants Majin are infertile (PMID: 26548954). In humans, biallelic mutations in MAJIN have been reported in infertile males.

ii) PMID: 33211200- A homozygous p.Arg53His in NOA-affected male (Individual 4- M1646) with high CADD scores and low gnomad freq. Mice disrupted for either Majin or Terb2 display impaired synapsis, zygotene arrest, a lack of postmeiotic cells and infertility (Shibuya et al. 2015; Zhang et al. 2017).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 C11orf80 Jasmine Chew gene: C11orf80 was added
gene: C11orf80 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: C11orf80 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C11orf80 were set to Recurrent hydatidiform mole 4, MIM # 618432
Review for gene: C11orf80 was set to AMBER
Added comment: Note: HGNC Approved Gene Symbol- TOP6BL

Literature in OMIM- PubMed: 30388401- Two unrelated females with RHMs carrying a homozygous p.Glu262∗ and p.Ser501Pro, respectively.

New paper (biallelic variants for OZEMA/NOA)
i) PMID: 36732965- A homozygous LOF p.E162* in four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility. Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 DNAAF4 Jasmine Chew gene: DNAAF4 was added
gene: DNAAF4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAAF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAAF4 were set to 23872636; 37674365; 37147940; 36583018; 35903363
Phenotypes for gene: DNAAF4 were set to Primary ciliary dyskinesia 25, MIM# 615482
Review for gene: DNAAF4 was set to GREEN
Added comment: Literature in OMIM- PMID: 23872636- biallelic variants reported for PCD, and reduced fertility was observed.

New papers (biallelic variants reported for PCD/ infertility):
i) PMID: 37674365- A novel homozygous splice acceptor site variant in DNAAF4 in two brother with asthenozoospermia. Functional assay revealed the absence of any exon 7-containing DNAAF4 transcripts in the sperm from P1, unlike in a normal control sample, consistent with the dysfunction or loss of DNAAF4 protein expression that may explain the abnormal sperm phenotypes in this patient.

ii) PMID: 37147940- Novel compound heterozygous splice site c.784-1G>A and 20.1 Kb deletion in a male with PCD and asthenoteratozoospermia, resulting in a truncated and functionless DNAAF4 protein. mmunofluorescence analysis indicated that the inner dynein arm was not present in the sperm flagellum, and sperm morphological analysis revealed small sperm with twisted and curved flagella or lacking flagella.

iii) PMID: 36583018- A novel homozygous p. G373E variant in a female patient with PCD who was born in a consanguineous family. Functional assays showed that the variant lead to PCD by reducing the stability of DNAAF4 protein.

iv) PMID: 35903363- Two homozygous variants, Arg330Trp and p.Arg245*, identified in two unrelated male and female with PCD. The affected male had asthenoteratozoospermia while female with primary infertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 TBPL2 Jasmine Chew gene: TBPL2 was added
gene: TBPL2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TBPL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBPL2 were set to 37804378; 33966269; 33893736; 33541821
Phenotypes for gene: TBPL2 were set to Oocyte maturation arrest
Review for gene: TBPL2 was set to GREEN
Added comment: New papers reporting biallelic variants in infertile women:
i) PMID: 37804378- Compound heterozygous novel p.Arg268Ter and recurrent p.Arg233Ter in a female with impaired ovarian folliculogenesis. Structure prediction by molecular modeling demonstrated that three-dimensional structure of TBPL2 was destabilized in mutant proteins.

ii) PMID: 33966269- Homozygous missense mutation p.C299R in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family. Functional assays showed that the transcriptional level of ZP3 was not completely blocked but severely reduced by the regulation of the mutant TBPL2, while the transcriptional level of H2Bc was significantly reduced but to a less severe extent compared with that of ZP3, suggesting that the missense had a damage to the transcription initiation function of TBPL2 and its downstream targeted genes got involved in different degrees. The mutant protein also has less stability, which contributes to the lower activity of transcription initiation in the mutant form.

iii) PMID: 33893736- Homozygous splicing variant (c.788 + 3A>G) in two unrelated families characterized by oocyte maturation defects. Functional assays showed that the variant disrupted the integrity of TBPL2 mRNA and affected oocytes showed that vital genes for oocyte maturation and fertilization were widely and markedly downregulated, suggesting that a mutation in TBPL2, led to global gene alterations in oocytes; the same variant reported before in PMID: 33541821 in three affected females with diminished ovarian reserve from 3 independent families.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 MEI1 Jasmine Chew changed review comment from: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others- PMID: 32741963, PMID: 36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Literature; to: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others: PMID: 32741963;36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 MEI1 Jasmine Chew edited their review of gene: MEI1: Changed publications: 30388401, 38416203, 34037756, 36759719, 32741963, 36017582
Infertility and Recurrent Pregnancy Loss v0.77 MEI1 Jasmine Chew gene: MEI1 was added
gene: MEI1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MEI1 were set to 30388401
Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia
Review for gene: MEI1 was set to GREEN
Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA)

New papers (biallelic variants for OZEMA):
i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles.

ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

New papers (biallelic variants for NOA):
i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro.
- others- PMID: 32741963, PMID: 36017582

Note: Moderate evidence for OZEMA and HM in FeRGI database
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 FOXL2 Jasmine Chew gene: FOXL2 was added
gene: FOXL2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FOXL2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FOXL2 were set to 12149404; 19429596; 38558253; 36793102; 39545410
Phenotypes for gene: FOXL2 were set to Premature ovarian failure 3, #MIM 608996
Added comment: Literature in OMIM- PubMed: 12149404; 19429596- multiple patients with isolated POF carrying monoallelic variants

New papers (monoallelic variants for POI):
i) PMID: 38558253- One in-frame deletion and 13 missense variants, including two recurrent ones (p.(Pro212Ala) and p.(Arg349Gly) in 14 patients with POI/DOR. Two variants, (p.(Gly187Asp) and p.(Arg349Gly) have been previously identified in patients with non-syndromic POI (PMID: 19429596 and PMID: 36793102).

ii) PMID: 36793102- Sixteen POI patients carrying four different heterozygous variants, including the recurrent p.(Arg349Gly). Functional assay on the recurrent variant showed that the mutant FOXL2 did not present with the transcriptional repressive effect on CYP17A1 expression as shown by wild-type protein.

New paper (biallelic variants for HM):
i) PMID: 39545410- A novel homozygous missense p.(Phe167Ser) in patient 1690 (South Asian) with 5 CHMs, 3 miscarriages, 1 stillbirth, and 1 live birth. FOXL2 is essential for granulosa cell differentiation and proliferation, as well as ovarian maintenance and function.Therefore, its impairment may affect indirectly the meiotic maturation of oocytes, and may consequently lead to molar pregnancies.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.77 NLRP7 Zornitza Stark Marked gene: NLRP7 as ready
Infertility and Recurrent Pregnancy Loss v0.77 NLRP7 Zornitza Stark Gene: nlrp7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.77 NLRP7 Zornitza Stark Classified gene: NLRP7 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.77 NLRP7 Zornitza Stark Gene: nlrp7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.76 MOS Zornitza Stark Marked gene: MOS as ready
Infertility and Recurrent Pregnancy Loss v0.76 MOS Zornitza Stark Gene: mos has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.76 MOS Zornitza Stark Classified gene: MOS as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.76 MOS Zornitza Stark Gene: mos has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.75 MUSK Zornitza Stark Marked gene: MUSK as ready
Infertility and Recurrent Pregnancy Loss v0.75 MUSK Zornitza Stark Added comment: Comment when marking as ready: Severe fetal anomalies can lead to pregnancy loss; however, this is more in scope for the Fetal Anomalies panel.
Infertility and Recurrent Pregnancy Loss v0.75 MUSK Zornitza Stark Gene: musk has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.75 MUSK Zornitza Stark Classified gene: MUSK as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.75 MUSK Zornitza Stark Gene: musk has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.74 DNAH11 Zornitza Stark Marked gene: DNAH11 as ready
Infertility and Recurrent Pregnancy Loss v0.74 DNAH11 Zornitza Stark Gene: dnah11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.74 DNAH11 Zornitza Stark Classified gene: DNAH11 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.74 DNAH11 Zornitza Stark Gene: dnah11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.73 LHCGR Zornitza Stark Marked gene: LHCGR as ready
Infertility and Recurrent Pregnancy Loss v0.73 LHCGR Zornitza Stark Gene: lhcgr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.73 LHCGR Zornitza Stark Classified gene: LHCGR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.73 LHCGR Zornitza Stark Gene: lhcgr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.72 FRAS1 Zornitza Stark Marked gene: FRAS1 as ready
Infertility and Recurrent Pregnancy Loss v0.72 FRAS1 Zornitza Stark Added comment: Comment when marking as ready: Severe fetal abnormalities can cause pregnancy loss. However, this is more in scope for Fetal anomalies panel.
Infertility and Recurrent Pregnancy Loss v0.72 FRAS1 Zornitza Stark Gene: fras1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.72 FRAS1 Zornitza Stark Classified gene: FRAS1 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.72 FRAS1 Zornitza Stark Gene: fras1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Marked gene: GBE1 as ready
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Added comment: Comment when marking as ready: Mechanism of pregnancy loss unclear, could be chance observation.
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Gene: gbe1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Marked gene: GBE1 as ready
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Gene: gbe1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Classified gene: GBE1 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.71 GBE1 Zornitza Stark Gene: gbe1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.70 FOXP3 Zornitza Stark Marked gene: FOXP3 as ready
Infertility and Recurrent Pregnancy Loss v0.70 FOXP3 Zornitza Stark Gene: foxp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.70 FOXP3 Zornitza Stark Classified gene: FOXP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.70 FOXP3 Zornitza Stark Gene: foxp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.69 FGA Zornitza Stark Marked gene: FGA as ready
Infertility and Recurrent Pregnancy Loss v0.69 FGA Zornitza Stark Added comment: Comment when marking as ready: Variants are missense/indels with limited other supporting information, hence Amber rating.
Infertility and Recurrent Pregnancy Loss v0.69 FGA Zornitza Stark Gene: fga has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.69 FGA Zornitza Stark Classified gene: FGA as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.69 FGA Zornitza Stark Gene: fga has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.68 KPNA7 Zornitza Stark Marked gene: KPNA7 as ready
Infertility and Recurrent Pregnancy Loss v0.68 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.68 KPNA7 Zornitza Stark Classified gene: KPNA7 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.68 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.67 CHEK1 Zornitza Stark Marked gene: CHEK1 as ready
Infertility and Recurrent Pregnancy Loss v0.67 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.67 CHEK1 Zornitza Stark Classified gene: CHEK1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.67 CHEK1 Zornitza Stark Gene: chek1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.66 BTG4 Zornitza Stark Marked gene: BTG4 as ready
Infertility and Recurrent Pregnancy Loss v0.66 BTG4 Zornitza Stark Gene: btg4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.66 BTG4 Zornitza Stark Classified gene: BTG4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.66 BTG4 Zornitza Stark Gene: btg4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.65 ASTL Zornitza Stark Marked gene: ASTL as ready
Infertility and Recurrent Pregnancy Loss v0.65 ASTL Zornitza Stark Gene: astl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.65 ASTL Zornitza Stark Classified gene: ASTL as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.65 ASTL Zornitza Stark Gene: astl has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.64 AIRE Zornitza Stark Marked gene: AIRE as ready
Infertility and Recurrent Pregnancy Loss v0.64 AIRE Zornitza Stark Gene: aire has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.64 AIRE Zornitza Stark Classified gene: AIRE as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.64 AIRE Zornitza Stark Gene: aire has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.63 CYP19A1 Jasmine Chew gene: CYP19A1 was added
gene: CYP19A1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CYP19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP19A1 were set to 32318648
Phenotypes for gene: CYP19A1 were set to Aromatase deficiency, MIM# 613546
Review for gene: CYP19A1 was set to GREEN
Added comment: Primary amenorrhea (feature of POI) and hypergonadotropic hypogonadism are observed in the presence of aromatase deficiency.

New papers:
i) PMID: 32318648- Novel biallelic CYP19A1 variants in 4 girls manifesting either at birth with atypical genitalia or puberty with poor breast development, clitoromegaly, abnormal menstrual bleeding, polycystic ovaries, and ovarian torsion. All variants except one missense showed a LOF. Protein structure and dynamics studies were in line with functional assays. The 2 female patients with delins variants manifested with ambiguous genitalia at birth. Histologic investigation revealed normal ovarian tissue on one side and a streak gonad on the other. Two female patients presented with abnormal pubertal development and polycystic ovaries.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 CYP17A1 Jasmine Chew changed review comment from: Primary amenorrhea is a feature of POI/POF- Literature in OMIM- PubMed: 15811924- homozygous truncating p.Y27X in a 20-yr-old female Turkish patient (46,XX) presented with primary amenorrhea, sexual infantilism, and easy fatigability. The patient's steroid metabolism showed increased levels of mineralocorticoid precursors and low or undetectable plasma concentrations of 17-alpha-hydroxycorticoids, androgens, and estrogens before and after ACTH stimulation.

New papers reported female with primary infertility (PI):
i) PMID: 36385415-reported a case (C29) with PI and recurrent implantation failure (RIF) carrying a homozygous missense p.Arg496His called likely pathogenic.

ii) PMID: 39039557- Two Caucasian Israeli-Arab females with PI carrying homozygous missense P.Arg496Cys.
Sources: Literature; to: Primary amenorrhea is a feature of POI/POF, which is present in 17-alpha-hydroxylase/17,20-lyase deficiency.

Literature in OMIM- PubMed: 15811924- homozygous truncating p.Y27X in a 20-yr-old female Turkish patient (46,XX) presented with primary amenorrhea, sexual infantilism, and easy fatigability. The patient's steroid metabolism showed increased levels of mineralocorticoid precursors and low or undetectable plasma concentrations of 17-alpha-hydroxycorticoids, androgens, and estrogens before and after ACTH stimulation.

New papers reported female with primary infertility (PI):
i) PMID: 36385415-reported a case (C29) with PI and recurrent implantation failure (RIF) carrying a homozygous missense p.Arg496His called likely pathogenic.

ii) PMID: 39039557- Two Caucasian Israeli-Arab females with PI carrying homozygous missense P.Arg496Cys.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 CYP17A1 Jasmine Chew gene: CYP17A1 was added
gene: CYP17A1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CYP17A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYP17A1 were set to 17-alpha-hydroxylase/17,20-lyase deficiency, MIM# 202110
Review for gene: CYP17A1 was set to GREEN
Added comment: Primary amenorrhea is a feature of POI/POF- Literature in OMIM- PubMed: 15811924- homozygous truncating p.Y27X in a 20-yr-old female Turkish patient (46,XX) presented with primary amenorrhea, sexual infantilism, and easy fatigability. The patient's steroid metabolism showed increased levels of mineralocorticoid precursors and low or undetectable plasma concentrations of 17-alpha-hydroxycorticoids, androgens, and estrogens before and after ACTH stimulation.

New papers reported female with primary infertility (PI):
i) PMID: 36385415-reported a case (C29) with PI and recurrent implantation failure (RIF) carrying a homozygous missense p.Arg496His called likely pathogenic.

ii) PMID: 39039557- Two Caucasian Israeli-Arab females with PI carrying homozygous missense P.Arg496Cys.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 AIRE Jasmine Chew gene: AIRE was added
gene: AIRE was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AIRE were set to 39318439; 38808199; 30150985
Phenotypes for gene: AIRE were set to Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia, MIM# 240300
Review for gene: AIRE was set to GREEN
Added comment: Hypogonadism in both males and females

New papers reporting biallelic variants in affected females with POI as part of the clinical manifestation of Autoimmune Polyglandular Syndrome 1- PMID: 39318439; 38808199; 30150985
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 LHCGR Jasmine Chew edited their review of gene: LHCGR: Changed publications: 10714363, 8559204, 21683950, 39162678, 37462066, 32860205, 29912377, 30016538
Infertility and Recurrent Pregnancy Loss v0.63 LHCGR Jasmine Chew gene: LHCGR was added
gene: LHCGR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: LHCGR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LHCGR were set to 10714363, 8559204, 21683950; 39162678; 37462066; 32860205; 29912377; 30016538
Phenotypes for gene: LHCGR were set to Luteinizing hormone resistance, female/ Leydig cell hypoplasia with pseudohermaphroditism/ Leydig cell hypoplasia with hypergonadotropic hypogonadism, MIM# 238320
Review for gene: LHCGR was set to GREEN
Added comment: Literature in OMIM- PMID:10714363, 8559204, 21683950

New papers:
i) PMID: 39162678- most recent review paper on LHCGR inactivating variants and reported phenotypes for affected males and females- oligoazoospermia and infertility with arrested spermatogenesis observed in some male patients and oligo-amenorrhea, anovulatory infertility, and failure of oocyte retrieval with hCG treatment despite multi-follicular development on ovulation induction in almost all females

ii)PMID: 37462066, PMID: 32860205, PMID: 29912377- novel biallelic variants in affected females with with empty follicle syndrome

iii) PMID: 30016538- homozygous truncating variant associated with primary ovarian insufficiency

Note: strong evidence for Oocyte/zygote/embryo maturation arrest (OZEMA) and moderate evidence for POI in FeRGI database.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 PATL2 Jasmine Chew edited their review of gene: PATL2: Changed phenotypes: Oocyte/zygote/embryo maturation arrest 4, MIM# 617743
Infertility and Recurrent Pregnancy Loss v0.63 RNF212B Jasmine Chew edited their review of gene: RNF212B: Changed phenotypes: Female and male infertility with recurrent medically assisted reproduction (MAR) failures
Infertility and Recurrent Pregnancy Loss v0.63 RNF212B Jasmine Chew gene: RNF212B was added
gene: RNF212B was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to 40259604; 37124137
Phenotypes for gene: RNF212B were set to Female and male infertility with recurrent medically assisted reproduction (MAR) failures.
Review for gene: RNF212B was set to AMBER
Added comment: Based on available evidence so far, it seems to be affecting Ashkenazi
Jewish population specifically:

i) PMID: 40259604- homozygous stop gained variant p.Arg150Ter in a young Ashkenazi Jewish female with a history of RPL underwent five in vitro fertilization cycles with nearly complete arrest of blastocyst development and ubiquitous aneuploidy of maternal origin in arrested embryos.

ii) PMID: 37124137- homozygous nonsense variant R150X in two brothers of Turkish Jewish descent and one unrelated Ashkenazi Jewish male with oligoasthenotheratozoospermia and infertility who had undergone numerous fertility treatments and failed IVF cycles. Single-cell RNA sequencing data analysis demonstrated expression of the pathogenic variant during various steps of spermatogenesis and consequent severe genomic instability in their sperm and embryos.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 PDCD2 Jasmine Chew gene: PDCD2 was added
gene: PDCD2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD2 were set to 40208938
Phenotypes for gene: PDCD2 were set to Non-immune hydrops fetalis, MONDO:0009369; Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: PDCD2 was set to AMBER
Added comment: PMID: 40208938- Novel biallelic PDCD2 variants associated with hydrops fetalis and early pregnancy loss in two affected families. Family 1 with RPL had three fetuses with NIHF who were all homozygous for p.(Pro28Ser) in PDCD2, while Family 2 had p.(Pro28Ser) in trans with p.(Arg34Pro) in two fetuses with NIHF. Family 2 was additionally notable for having a healthy child who was homozygous for the reference allele, consistent with appropriate disease segregation with the PDCD2 variants. Functional studies using primary fetal fibroblasts and human cell lines for both variants showed reduced PDCD2 mRNA level in affected patients' fibroblasts, reduced cellular accumulation of mutant proteins with impaired ability to associate with the 40S subunit ribosomal protein uS5, and further depletion of PDCD2 in fibroblast cells severely impacted ribosome biogenesis. It is notable that formation of the PDCD2-uS5 complex was not completely abolished by the patient variants and that rRNA processing was only partially impaired, as indicated by levels of 40S pre-rRNAs. We thus suspect that the PDCD2 pathogenic variants p.(Pro28Ser) and p.(Arg34Pro) are hypomorphic alleles, with a low level of residual function allowing for cellular differentiation and growth to a certain extent.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 MUSK Jasmine Chew gene: MUSK was added
gene: MUSK was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MUSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MUSK were set to 25612909; 25537362; 31750350; 38566418
Phenotypes for gene: MUSK were set to Fetal akinesia deformation sequence 1, MIM# 208150
Review for gene: MUSK was set to AMBER
Added comment: i) PMID: 25612909- First to report homozygous frameshift variant p.Thr14Asnfs*9 in all affected fetuses with FADS in an affected family which also has two miscarriages. This variant leads to a complete loss of protein expression. Of note, incomplete loss of MuSK function will cause a CMS phenotype, whereas complete loss of function is lethal.

ii) PMID: 25537362- Homozygous missense variant p.Ile575Thr in the intracellular domain of MUSK in 11 out of 14 affected fetuses with lethal FADS (only 11 have DNA available) with a common ancestry from 11 families, suggesting founder effect.

iii) PMID: 31750350- Compound heterozygous variants in an affected fetus with lethal FADS (the mother also had previous abortion due to similarly affected fetus)

iv) Ding et al, 2020 (DOI: 10.22541/au.160097884.45196854)-novel compound heterozygous in a FADS affected fetus (mother also had two previous pregnancies with similarly affected fetuses, terminated)

v) PMID: 38566418- Reviewed previously reported MUSK pathogenic variants (46 patients in total with 29 unique disease-causing variants) appeared in four of the seven MuSK domains, including the Ig1, Frz-like, juxtamembrane, and kinase domains. Homozygous loss-of-function variants resulted in the most severe phenotype (FADS).

Note: Classified as amber since most of the reported cases were TOP rather than IUFD.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 CHRNA1 Jasmine Chew changed review comment from: Spontaneous abortion reported before.

New papers:
i) PMID: 23037934- A novel homozygous p.R254C variant in a family with recurrent fetal loss due to NIHF.

ii) PMID: 18252226- Family CHRNA1-F1 had a family history of spontaneous abortions (IV-2 within the family) and two of the affected fetus (IV-1 stillbirth and IV-3 TOP) carried homozygous R234L.
Sources: Literature; to: Spontaneous abortion reported before.

Other papers:
i) PMID: 23037934- A novel homozygous p.R254C variant in a family with recurrent fetal loss due to NIHF.

ii) PMID: 18252226- Family CHRNA1-F1 had a family history of spontaneous abortions (IV-2 within the family) and two of the affected fetus (IV-1 stillbirth and IV-3 TOP) carried homozygous R234L.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 CHRNA1 Jasmine Chew gene: CHRNA1 was added
gene: CHRNA1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CHRNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA1 were set to 23037934; 18252226
Phenotypes for gene: CHRNA1 were set to Multiple pterygium syndrome, lethal type, MIM# 253290
Added comment: Spontaneous abortion reported before.

New papers:
i) PMID: 23037934- A novel homozygous p.R254C variant in a family with recurrent fetal loss due to NIHF.

ii) PMID: 18252226- Family CHRNA1-F1 had a family history of spontaneous abortions (IV-2 within the family) and two of the affected fetus (IV-1 stillbirth and IV-3 TOP) carried homozygous R234L.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TTN Jasmine Chew changed review comment from: i) PMID: 36977548- Reported 10 cases from six unrelated families showing different TTN combinations and four of those cases (F3-iii.1, F6-II.1, F6.ii.3, F6.ii.4) died in utero between 2nd-3rd trimester.
- Quoted that "Probably, we are still missing the most severe end spectrum of titinopathies, as we are used to studying fetuses from late miscarriages or dead infants, while only few investigations are usually performed on early miscarriages. Moreover, prenatal tests often do not include TTN sequencing."

ii)PMID: 38148006- com het p.Arg33743Ter and p.Gln34752Ter in a fetus with with hydrops fetalis and arthrogryposis multiplex congenita, which died in utero in 3rd trimester.

iii) PMID: 29575618- homozygous c.36122delC (p. P12041Lfs*20) variant in 8 members of a consanguineous family affected with a lethal congenital contracture syndrome and among those 8, 3 were IUFD.
Sources: Literature; to: i) PMID: 36977548- Reported 10 cases from six unrelated families showing different TTN combinations and four of those cases (F3-iii.1, F6-II.1, F6.ii.3, F6.ii.4) died in utero between 2nd-3rd trimester.
- Quoted that "Probably, we are still missing the most severe end spectrum of titinopathies, as we are used to studying fetuses from late miscarriages or dead infants, while only few investigations are usually performed on early miscarriages. Moreover, prenatal tests often do not include TTN sequencing."

ii)PMID: 38148006- com het p.Arg33743Ter and p.Gln34752Ter in a fetus with with hydrops fetalis and arthrogryposis multiplex congenita, which died in utero in 3rd trimester.

iii) PMID: 29575618- homozygous c.36122delC (p. P12041Lfs*20) variant in 8 members of a consanguineous family affected with a lethal congenital contracture syndrome and among those 8, three members were IUFD.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TTN Jasmine Chew gene: TTN was added
gene: TTN was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTN were set to 36977548; 38148006; 29575618
Phenotypes for gene: TTN were set to Lethal congenital contracture syndrome, MONDO:0017436
Review for gene: TTN was set to GREEN
Added comment: i) PMID: 36977548- Reported 10 cases from six unrelated families showing different TTN combinations and four of those cases (F3-iii.1, F6-II.1, F6.ii.3, F6.ii.4) died in utero between 2nd-3rd trimester.
- Quoted that "Probably, we are still missing the most severe end spectrum of titinopathies, as we are used to studying fetuses from late miscarriages or dead infants, while only few investigations are usually performed on early miscarriages. Moreover, prenatal tests often do not include TTN sequencing."

ii)PMID: 38148006- com het p.Arg33743Ter and p.Gln34752Ter in a fetus with with hydrops fetalis and arthrogryposis multiplex congenita, which died in utero in 3rd trimester.

iii) PMID: 29575618- homozygous c.36122delC (p. P12041Lfs*20) variant in 8 members of a consanguineous family affected with a lethal congenital contracture syndrome and among those 8, 3 were IUFD.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 STIL Jasmine Chew changed review comment from: PMID: 29230157- In a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum, compound heterozygous missense variants (p.H411D and p.M124V) identified in two affected male fetuses with partial agenesis of the corpus callosum. Concluded that the compound heterozygous STIL mutations found by WES in the affected fetuses cause the severe neurodevelopmental defects observed by fetal ultrasound and MRI, possibly also causing the recurrent miscarriages for the couple. The 5 miscarriages occurring in the family may suggest a causal relationship between the STIL mutations and embryonic lethality in humans.

ii) PMID: 33772059- A homozygous missense variant p.338H>Y in case 93272, an Iranian family with 4 miscarriages. Fetal autopsy not available for this family. PMID: 10385121 disrupted STIL in mice and the homozygous mutant caused death with neural tube defects, holoprosencephaly and left–right development abnormalities during embryonic development.
Sources: Literature; to: i) PMID: 29230157- In a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum, compound heterozygous missense variants (p.H411D and p.M124V) identified in two affected male fetuses with partial agenesis of the corpus callosum. Functional study showed impairment of the normal regulation of centriole lengthening. Concluded that the compound heterozygous STIL mutations found by WES in the affected fetuses cause the severe neurodevelopmental defects observed by fetal ultrasound and MRI, possibly also causing the recurrent miscarriages for the couple. The 5 miscarriages occurring in the family may suggest a causal relationship between the STIL mutations and embryonic lethality in humans.

ii) PMID: 33772059- A homozygous missense variant p.338H>Y in case 93272, an Iranian family with 4 miscarriages. Fetal autopsy not available for this family. PMID: 10385121 disrupted STIL in mice and the homozygous mutant caused death with neural tube defects, holoprosencephaly and left–right development abnormalities during embryonic development.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 STIL Jasmine Chew changed review comment from: PMID: 29230157- In a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum, compound heterozygous missense variants (p.H411D and p.M124V) identified in two affected male fetuses with partial agenesis of the corpus callosum. Concluded that the compound heterozygous STIL mutations found by WES in the affected fetuses cause the severe neurodevelopmental defects observed by fetal ultrasound and MRI, possibly also causing the recurrent miscarriages for the couple. The 5 miscarriages occurring in the family may suggest a causal relationship between the STIL mutations and embryonic lethality in humans.

ii) PMID: 33772059- A homozygous missense variant p.338H>Y in case 93272, an Iranian family with 4 miscarriages. Fetal autopsy not available for this family. PMID: 10385121 disrupted STIL in mice and the homozygous mutant caused death with neural tube defects, holoprosencephaly and left–right development abnormalities during embryonic development
Sources: Literature; to: PMID: 29230157- In a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum, compound heterozygous missense variants (p.H411D and p.M124V) identified in two affected male fetuses with partial agenesis of the corpus callosum. Concluded that the compound heterozygous STIL mutations found by WES in the affected fetuses cause the severe neurodevelopmental defects observed by fetal ultrasound and MRI, possibly also causing the recurrent miscarriages for the couple. The 5 miscarriages occurring in the family may suggest a causal relationship between the STIL mutations and embryonic lethality in humans.

ii) PMID: 33772059- A homozygous missense variant p.338H>Y in case 93272, an Iranian family with 4 miscarriages. Fetal autopsy not available for this family. PMID: 10385121 disrupted STIL in mice and the homozygous mutant caused death with neural tube defects, holoprosencephaly and left–right development abnormalities during embryonic development.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 STIL Jasmine Chew gene: STIL was added
gene: STIL was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: STIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STIL were set to 29230157; 33772059
Phenotypes for gene: STIL were set to Recurrent pregnancy loss susceptibility, MONDO:0000144; Primary microcephaly 7, autosomal recessive, MIM# 612703
Review for gene: STIL was set to AMBER
Added comment: PMID: 29230157- In a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum, compound heterozygous missense variants (p.H411D and p.M124V) identified in two affected male fetuses with partial agenesis of the corpus callosum. Concluded that the compound heterozygous STIL mutations found by WES in the affected fetuses cause the severe neurodevelopmental defects observed by fetal ultrasound and MRI, possibly also causing the recurrent miscarriages for the couple. The 5 miscarriages occurring in the family may suggest a causal relationship between the STIL mutations and embryonic lethality in humans.

ii) PMID: 33772059- A homozygous missense variant p.338H>Y in case 93272, an Iranian family with 4 miscarriages. Fetal autopsy not available for this family. PMID: 10385121 disrupted STIL in mice and the homozygous mutant caused death with neural tube defects, holoprosencephaly and left–right development abnormalities during embryonic development
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TIMP2 Jasmine Chew gene: TIMP2 was added
gene: TIMP2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TIMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIMP2 were set to 20847186; 34756330
Phenotypes for gene: TIMP2 were set to Recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: TIMP2 was set to AMBER
Added comment: i) PMID: 20847186- In family 6, TIMP2 partial duplication (involves Ex1-2) in mother and 4 out of 5 miscarriages. They have not yet been associated with RPL in humans, however, overexpression of TIMP2 was detected in a mouse model of RPL (Dixon et al., 2006). The TIMP2 disruption in miscarriages in Family 6 may have affected the placental development, but the possibility remains that maternal disruption of TIMP2 may contribute to RPL by impairing the remodeling of the endometrium in early pregnancy. Functional study was performed by PMID: 25674159, which showed reduced RNA and protein expression in chorionic villi cultures from miscarriages with the CNV.

ii) PMID: 34756330- de novo damaging heterozygous missense TIMP2 variant, c.[553G>A]; p.[Gly185Arg] in an eight-week euploid embryonic loss. The MMP2/TIMP2 complex is involved in several gestational processes including implantation and placentation.

iii) PMID: 11912288- The disruption of the TIMP2 gene was considered to be relevant for recurrent miscarriage due to its critical role in modulating invasion of the trophoblast into maternal endometrium and in vascular remodeling and angiogenesis of maternal and placenta tissues in the first trimester.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 KIF14 Jasmine Chew edited their review of gene: KIF14: Changed phenotypes: Autosomal recessive lethal fetal ciliopathy
Infertility and Recurrent Pregnancy Loss v0.63 KIF14 Jasmine Chew gene: KIF14 was added
gene: KIF14 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to 24128419; 30388224
Review for gene: KIF14 was set to GREEN
Added comment: i) PMID: 24128419- First human phenotype associated with biallelic inactivating mutations of KIF14, reported 2 affected fetuses in a family with a recurrent fetal pattern of multiple congenital anomalies (MCA), which was considered to be lethal because of distinct brain and kidney malformations, which were both terminated before 20 weeks carrying LOF com het p.Glu584Ilefs*16 and p.Arg594*.Very recently, homozygous mutations in Kif14 (G/A substitution at the 3′ splice acceptor site of Kif14 exon 5) were identified in a novel spontaneous mouse mutant, laggard (lag). which recapitulated most of the fetal phenotypes including the brain malformations, reduced brain size, general growth restriction and early lethality seen in this family (PMID: 23308235).

ii) PMID: 30388224- Novel biallelic KIF14 variants in fetuses (IUFD) from 4 unrelated families presenting with strikingly similar severe brain and kidney phenotypes- renal hypodysplasia and microcephaly, diagnosed as lethal, highly penetrant syndromic CAKUT with microcephaly. Functional studies using transfection study and zebrafish models are supportive that loss of KIF14 result in defects in cytokinesis, microcephaly and ciliopathy-related phenotypes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 GBE1 Jasmine Chew gene: GBE1 was added
gene: GBE1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 33772059; 25489661; 26166723
Phenotypes for gene: GBE1 were set to Glycogen storage disease IV, MIM# 232500
Review for gene: GBE1 was set to GREEN
Added comment: i) PMID: 33772059- one Iranian family with RPL (Fam 90759 , a 13-week fetus with hydrops fetalis observed in ultrasonography) carrying compound heterozygous p.156R>H and c.-35_-54del GCTCAGGCCCCACTCGACCC.

ii) PMID: 25489661- compound heterozygous c.1937delT and c.691+2T>C in a female with spontaneous miscarriage at 8 weeks of gestation with diagnosis of Glycogen storage disease type IV (GSD IV) supported by pathological examination of immature villi.

iii) PMID: 26166723-ompound heterozygous c.691+2T>C and p.R524X in A 30-yr-old woman presented with 2 consecutive miscarriages within 7 month with diagnosis of Glycogen storage disease type IV (GSD IV) supported by pathological examination of placental tissues. Concluded that glycogen storage disease Type IV can cause early miscarriage and that diagnosis can initially be made on histopathologic examination.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 SCN5A Jasmine Chew gene: SCN5A was added
gene: SCN5A was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SCN5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SCN5A were set to 33772059; 32421437; 23571586; 15184283
Review for gene: SCN5A was set to GREEN
Added comment: i) PMID: 33772059- An Iranian family with RPL (Fam 94947) without fetal autopsy carrying homozygous missense p.1250T>M. The parents were both carriers with a history of cardiac events in the family. This variant has been reported to cause long QT syndrome 3 (LQT3) (#603830) in the heterozygous state. Homozygous mutations in SCN5A in mice cause intrauterine lethality mostly during organogenesis due to heart defects (PMID: 11972032).

ii) PMID: 32421437- de novo SCN5A variants in four cases which all died and three of them died in utero.

iii) PMID: 23571586- 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases).

iv) PMID: 15184283- A case of recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome- low level mosaic R1623Q present in mom and cord blood from the third fetus also harbored the mutant allele, suggesting that all 3 cases of late-term fetal distress resulted from germ-line transfer of the LQTS-associated mutation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 FRAS1 Jasmine Chew changed review comment from: New papers:
i) PMID: 33772059- An Iranian family with RPL (Fam 90377 with fetal autopsy showing 17 weeks male with Fraser syndrome and Bartsocas-Papas syndrome- syndactyly, dysplastic ears, right kidney agenesis, club foot, flexion contracture of the hip, and atretic external auditory canals) carrying a homozygous missense variant, p.135T>M.

ii) PMID: 32643034- Four affected fetus from 4 independent families carrying novel homozygous LOF variants (p.His2995Profs*3, c.9780+2T>C, c.8098+2T>A, c.5217+1G>C) All these affected families had history of miscarriages/ intrauterine fetal loss.
Sources: Literature; to: New papers:
i) PMID: 33772059- An Iranian family with RPL (Fam 90377 with fetal autopsy showing 17 weeks male with Fraser syndrome and Bartsocas-Papas syndrome- syndactyly, dysplastic ears, right kidney agenesis, club foot, flexion contracture of the hip, and atretic external auditory canals) carrying a homozygous missense variant, p.135T>M.

ii) PMID: 32643034- Four affected fetus from 4 independent families carrying novel homozygous LOF variants (p.His2995Profs*3, c.9780+2T>C, c.8098+2T>A, c.5217+1G>C) All these affected families had history of miscarriages/ intrauterine fetal loss due to oligohydramnios, renal agenesis and other congenital anomalies.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 FRAS1 Jasmine Chew gene: FRAS1 was added
gene: FRAS1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FRAS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRAS1 were set to 33772059; 32643034
Phenotypes for gene: FRAS1 were set to Fraser syndrome 1, MIM# 219000
Review for gene: FRAS1 was set to GREEN
Added comment: New papers:
i) PMID: 33772059- An Iranian family with RPL (Fam 90377 with fetal autopsy showing 17 weeks male with Fraser syndrome and Bartsocas-Papas syndrome- syndactyly, dysplastic ears, right kidney agenesis, club foot, flexion contracture of the hip, and atretic external auditory canals) carrying a homozygous missense variant, p.135T>M.

ii) PMID: 32643034- Four affected fetus from 4 independent families carrying novel homozygous LOF variants (p.His2995Profs*3, c.9780+2T>C, c.8098+2T>A, c.5217+1G>C) All these affected families had history of miscarriages/ intrauterine fetal loss.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 PIEZO1 Jasmine Chew gene: PIEZO1 was added
gene: PIEZO1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PIEZO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIEZO1 were set to 33772059; 30244526; 26333996
Phenotypes for gene: PIEZO1 were set to Lymphatic malformation 6, MIM# 616843
Review for gene: PIEZO1 was set to GREEN
Added comment: i) PMID: 33772059- Two unrelated Iranian families with RPL carrying different biallelic variants (i. Fam 82169 with fetal autopsy showing generalized lymphatic dysplasia of Fotiou with non-immune fetal hydrops carry homozygous LOF c.30_31delAC, ii) fam 95136 without fetal autopsy carrying compound heterozygous p.2195S>L and p.922G>W).

ii) PMID: 30244526- Compound heterozygous variants p.Trp1069* and p.Lys2070Gln in a case of a woman with recurrent pregnancies affected by NIHF and had three fetal demises because of severe lymphatic dysplasia.

iii) PMID: 26333996- In a recent review of 10 patients within 6 families, 7 of the probands were diagnosed with NIHF, including 2 died in utero, carrying biallelic variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 BTG4 Jasmine Chew gene: BTG4 was added
gene: BTG4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BTG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BTG4 were set to 32502391; 34647228
Phenotypes for gene: BTG4 were set to Oocyte/zygote/embryo maturation arrest 8, MIM# 619009
Review for gene: BTG4 was set to GREEN
Added comment: Literature in OMIM- PMID: 32502391, 34647228- >3 unrelated infertile women due to failure of the fertilized ovum to undergo zygotic cleavage with different biallelic variants. Functional analysis demonstrated LOF, such as reduced mutant protein expression and disruption in the process of maternal mRNA decay, and loss of protein-protein interaction.

New paper:
i) PMID: 36471203- A novel homozygous truncating variant (p.V195Sfs) in a a female patient with primary infertility and recurrent failure of IVF with zygotic cleavage failure. Co-immunoprecipitation in 293 T cells showed that the mutation abolished the interaction between BTG4 and PABPN1L.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 NLRP2 Jasmine Chew gene: NLRP2 was added
gene: NLRP2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NLRP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP2 were set to 30877238; 39585517; 39905760
Phenotypes for gene: NLRP2 were set to Oocyte/zygote/embryo maturation arrest 18, MIM# 620332
Review for gene: NLRP2 was set to GREEN
Added comment: Literature in OMIM- PMID: 30877238 (>3 unrelated infertile women due to early embryonic arrest with different biallelic variants)

New papers (biallelic variants for EEA):
i) PMID: 39585517- A novel homozygous protein-truncating (p.Tyr66Thrfs*32) in an infertile female with early embryonic arrest, which resulted in the down-regulation of NLRP2 mRNA expression, truncation of the protein structure, and altered protein localization in cells.

ii) PMID: 39905760- Novel compound heterozygous protein-truncating variants ( p.Leu443Phefs*78 and p.Arg935Metfs*15) in a female with primary infertility, four early miscarriages, and one failed attempt of ICSI. The two variants mediate mRNA decay in EBV-transformed lymphoblastoid cells from the patient, lead to decreased NLRP2 protein levels, and alter NLRP2 interactions with other members of the SCMC in vitro.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 MOS Jasmine Chew gene: MOS was added
gene: MOS was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MOS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOS were set to 34779126; 34997960; 35670744; 36403623
Phenotypes for gene: MOS were set to Oocyte/zygote/embryo maturation arrest 20, MIM# 620383
Review for gene: MOS was set to GREEN
Added comment: Literature in OMIM- PMID: 34779126; 34997960; 35670744; 36403623- >3 unrelated women with infertility due to early/preimplantation embryonic arrest and fragmentation carrying different biallelic variants. All variants except I197M had functional evidence showing that mutant proteins showed reduced activation/phosphorylation of the MOS downstream targets compared to wildtype MOS.
Note: couldn't find new case reports
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 KPNA7 Jasmine Chew gene: KPNA7 was added
gene: KPNA7 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KPNA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KPNA7 were set to 36647821
Phenotypes for gene: KPNA7 were set to Oocyte/zygote/embryo maturation arrest 17, #MIM 620319
Review for gene: KPNA7 was set to GREEN
Added comment: Literature in OMIM- PMID:36647821- 10 Chinese women from 10 independent families with infertility due to preimplantation embryo arrest carrying the following biallelic variants: x6 homozygous L203F missense, x3 compound heterozygous L203F/P212L, L203F/Q175K, L203F/C451X, and x1 homozygous V152M. Western blot of transfected HEK293T cells showed that all mutant protein levels were significantly lower than wildtype KPNA7. Mutant KPNA7 showed significantly reduced SV40TNLS protein transport activity compared to wildtype KPNA7.
- There were no homozygotes for the recurrent L203F variant either in public databases or in-house control databases. Homozygosity mapping analysis suggested a low probability of founder effect for the recurrent variant L203F.

Note: couldn't find new case reports
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 CHEK1 Jasmine Chew edited their review of gene: CHEK1: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.63 CHEK1 Jasmine Chew gene: CHEK1 was added
gene: CHEK1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CHEK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK1 were set to 33953335; 33948904
Phenotypes for gene: CHEK1 were set to Oocyte/zygote/embryo maturation arrest 21, MIM# 620610
Added comment: Literature in OMIM- PMID: 33953335; 33948904
- >3 unrelated with infertility due to zygote/embryo cleavage arrest with three different missense variants and 1 1bp deletion. Functional studies using transfection studies showed that all mutant increased cytoplasmic localization significantly greater kinase activity. Injection of all mutant cRNA into mouse zygotes with 2 distinct pronuclei also resulted in significantly decreased cleavage rates compared to wildtype.

Note: couldn't find new case reports
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 ASTL Jasmine Chew gene: ASTL was added
gene: ASTL was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ASTL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTL were set to 34704130; 37640117; 37133443
Phenotypes for gene: ASTL were set to Oocyte/zygote/embryo maturation arrest 11, MIM# 619643
Review for gene: ASTL was set to GREEN
Added comment: Literature in OMIM- PMID: 34704130- One Saudi family with 2 sisters with reduced or absent fertility due to oocyte maturation defect carrying a homozygous splice variant.

New papers (biallelic variants)
i) PMID: 37640117 - Novel compound heterozygous missense variants (p.Arg117Cys and p.Arg274Trp) in a Chinese woman with primary infertility and polyspermy in IVF. Moreover, transfection studies using CHO-K1 cells indicated that mutant cells showed abnormal ovastacin zymogen activation or decreased enzyme stability.

ii) PMID: 37133443- Biallelic variants in four independent affected individuals with primary infertility. The frameshift variants significantly decreased the quantity of ASTL protein in vitro. And all missense variants affected the enzymatic activity that cleaves ZP2 in mouse egg in vitro. Three knock-in female mice (corresponding to three missense variants in patients) all show subfertility due to low embryo developmental potential.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 FOXP3 Jasmine Chew gene: FOXP3 was added
gene: FOXP3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FOXP3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FOXP3 were set to 28833278; 25546394; 26395338; 26387632; 26009232
Phenotypes for gene: FOXP3 were set to X-linked immunodysregulation, polyendocrinopathy, and enteropathy, MIM# 304790
Review for gene: FOXP3 was set to GREEN
Added comment: Multiple papers reported recurrent male miscarriages in different families:
i) PMID: 28833278- hemizygous truncating variant (p.D303fs*87) in a most recent male IUFD fetus (hydrops fetalis and fetal death around 18 GA weeks) in a family with recurrent IUFD of 19 males in total occurred at ≤20 weeks of gestation, and the same variant was carried by all five healthy obligatory female carriers. Recent studies involving patients with unexplained recurrent spontaneous abortions have demonstrated that downregulation of Treg cells may be due to a significant decrease in the expression of the FOXP3 gene due to epigenetic suppression of FOXP3 through promoter methylation, thus increasing the risk for IUFD (PMID: 27785899)

ii) PMID: 25546394- Two unrelated families with clear evidence of fetal-onset IPEX syndrome (Family 1 had a family history of five miscarriages of males in two generations, positive for hemizygous p.R397W, family 2 with first two males died prematurely after birth and miscarriage of two monochorionic male twins, positive for hemizygous truncating variant (p.S107Nfs*204).

iii) PMID: 26395338- A family with the loss of two male fetuses as a result of fetal hydrops of unknown etiology due to novel nonsense variant (p.R337*).

iv)PMID: 26387632- The same p.R337* in an unrelated family with multiple male miscarriages occurring around 18 to 20 weeks of EGA and associated with hydrops fetalis and fetal akinesia.

v) PMID: 26009232- A family with two miscarriages and three early IUFDs of male fetuses with hemizygous missense variant (p.L345F).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 STAR Jasmine Chew changed review comment from: Literature on variants associated with ovarian failure presented in unrelated classic lipoid adrenal hyperplasia (LAH) patients:
i) PMID: 38913505- Homozygous p.W147X, p.Arg182Cys, p.W250X, p.Gln258X, p.Leu260Pro, p.Leu275Pro with low/loss of function when tested in vitro.

ii) PMID: 36733346 - Novel compound heterozygous variants (p. Q258*/p. S186R)-p.Q258* generates a truncated protein while S186R disrupts STAR protein function. The residual STAR activities of p.S186R, p.Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins.
Sources: Literature; to: Literature on variants associated with ovarian failure presented in unrelated classic lipoid adrenal hyperplasia (LAH) patients:
i) PMID: 38913505- Homozygous p.W147X, p.Arg182Cys, p.W250X, p.Gln258X, p.Leu260Pro, p.Leu275Pro with low/loss of function when tested in vitro.

ii) PMID: 36733346 - Novel compound heterozygous variants (p. Q258*/p. S186R)-p.Q258* generates a truncated protein while S186R disrupts STAR protein function. The residual STAR activities of p.S186R, p.Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, of the wild-type protein activity, respectively.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 STAR Jasmine Chew gene: STAR was added
gene: STAR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAR were set to 38913505; 36733346
Phenotypes for gene: STAR were set to Lipoid adrenal hyperplasia, MIM# 201710
Review for gene: STAR was set to GREEN
Added comment: Literature on variants associated with ovarian failure presented in unrelated classic lipoid adrenal hyperplasia (LAH) patients:
i) PMID: 38913505- Homozygous p.W147X, p.Arg182Cys, p.W250X, p.Gln258X, p.Leu260Pro, p.Leu275Pro with low/loss of function when tested in vitro.

ii) PMID: 36733346 - Novel compound heterozygous variants (p. Q258*/p. S186R)-p.Q258* generates a truncated protein while S186R disrupts STAR protein function. The residual STAR activities of p.S186R, p.Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 SYCE1 Jasmine Chew changed review comment from: Literature in OMIM: PMIM: 25062452; 25899990; 26203179- biallelic variants reported for affected individuals with POI/spermatogenic failure (NOA)

New papers (biallelic variants for POI/NOA):
i) PMID: 36373164- Two POI/DOR patients with biallelic LOF variants (Patient II-1 in Family 3 with compound heterozygous variants c.154C > T (p.Arg52*) and c.675del (p.Asp226Metfs*29); Patient II-1 in Family 6 with a homozygous donor splicing variant c.271 + 1G > A which led to exon 4 skipping and indel mutant p.Ala66_Leu91delinsVal).

ii) PMID: 35718780- Two NOA-affected patients with different biallelic CNVs (patient 1- novel heterozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous LOF (p.F230fs), patient 2- homozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del).

iii) PMID: 34718620- Compound heterozygous variants (p.Glu159Lys and p.Phe230Serfs*21) in a POI patient and a homozygous variant (NM_001143764.3: c.271 + 2T > C) in a NOA patient.
Sources: Literature; to: Literature in OMIM: PMIM: 25062452; 25899990; 26203179- biallelic variants reported for affected individuals with POI/spermatogenic failure (NOA)

New papers (biallelic variants for POI/NOA):
i) PMID: 36373164- Two POI/DOR patients with biallelic LOF variants (Patient II-1 in Family 3 with compound heterozygous variants c.154C > T (p.Arg52*) and c.675del (p.Asp226Metfs*29); Patient II-1 in Family 6 with a homozygous donor splicing variant c.271 + 1G > A which led to exon 4 skipping and indel mutant p.Ala66_Leu91delinsVal).

ii) PMID: 35718780- Two NOA-affected patients with different biallelic CNVs (patient 1- novel heterozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous LOF (p.F230fs), patient 2- homozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del).

iii) PMID: 34718620- Compound heterozygous variants (p.Glu159Lys and p.Phe230Serfs*21) in a POI patient and a homozygous variant (NM_001143764.3: c.271 + 2T > C) in a NOA patient.
Sources: Literature
Mode of pathogenicity: Provide exceptions to loss-of-function
Infertility and Recurrent Pregnancy Loss v0.63 SYCE1 Jasmine Chew edited their review of gene: SYCE1: Changed mode of pathogenicity: Other; Changed phenotypes: Premature ovarian failure 12, MIM# 616947, Spermatogenic failure 15 ,MIM# 616950
Infertility and Recurrent Pregnancy Loss v0.63 SYCE1 Jasmine Chew edited their review of gene: SYCE1: Changed phenotypes: Premature ovarian failure 12, MIM# 616947, Spermatogenic failure 15 ,MIM#616950
Infertility and Recurrent Pregnancy Loss v0.63 SYCE1 Jasmine Chew changed review comment from: Literature in OMIM: PMIM: 25062452; 25899990; 26203179- biallelic variants reported for affected individuals with POI/spermatogenic failure (NOA)

New papers (biallelic variants for POI/NOA):
i) PMID: 36373164- Two POI/DOR patients with biallelic LOF variants (Patient II-1 in Family 3 with compound heterozygous variants c.154C > T (p.Arg52*) and c.675del (p.Asp226Metfs*29); Patient II-1 in Family 6 with a homozygous donor splicing variant c.271 + 1G > A which led to exon 4 skipping and indel mutant p.Ala66_Leu91delinsVal).

ii) PMID: 35718780- Two NOA-affected patients with different biallelic CNVs (patient 1- novel heterozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous LOF (p.F230fs), patient 2- homozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del).

iii) PMID: 34718620- Compound heterozygous variants (p.Glu159Lys and p.Phe230Serfs*21) in a POI patient and a homozygous variant (NM_001143764.3: c.271 + 2T > C) in a NOA patient.
Sources: Literature; to: Literature in OMIM: PMIM: 25062452; 25899990; 26203179- biallelic variants reported for affected individuals with POI/spermatogenic failure (NOA)

New papers (biallelic variants for POI/NOA):
i) PMID: 36373164- Two POI/DOR patients with biallelic LOF variants (Patient II-1 in Family 3 with compound heterozygous variants c.154C > T (p.Arg52*) and c.675del (p.Asp226Metfs*29); Patient II-1 in Family 6 with a homozygous donor splicing variant c.271 + 1G > A which led to exon 4 skipping and indel mutant p.Ala66_Leu91delinsVal).

ii) PMID: 35718780- Two NOA-affected patients with different biallelic CNVs (patient 1- novel heterozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous LOF (p.F230fs), patient 2- homozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del).

iii) PMID: 34718620- Compound heterozygous variants (p.Glu159Lys and p.Phe230Serfs*21) in a POI patient and a homozygous variant (NM_001143764.3: c.271 + 2T > C) in a NOA patient.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 SYCE1 Jasmine Chew gene: SYCE1 was added
gene: SYCE1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SYCE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCE1 were set to 25062452; 25899990; 26203179; 36373164; 35718780; 34718620
Phenotypes for gene: SYCE1 were set to Premature ovarian failure 12, MIM# 616947, Spermatogenic failure 15 ,MIM# 616950
Mode of pathogenicity for gene: SYCE1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: SYCE1 was set to GREEN
Added comment: Literature in OMIM: PMIM: 25062452; 25899990; 26203179- biallelic variants reported for affected individuals with POI/spermatogenic failure (NOA)

New papers (biallelic variants for POI/NOA):
i) PMID: 36373164- Two POI/DOR patients with biallelic LOF variants (Patient II-1 in Family 3 with compound heterozygous variants c.154C > T (p.Arg52*) and c.675del (p.Asp226Metfs*29); Patient II-1 in Family 6 with a homozygous donor splicing variant c.271 + 1G > A which led to exon 4 skipping and indel mutant p.Ala66_Leu91delinsVal).

ii) PMID: 35718780- Two NOA-affected patients with different biallelic CNVs (patient 1- novel heterozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous LOF (p.F230fs), patient 2- homozygous intragenic deletion (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del).

iii) PMID: 34718620- Compound heterozygous variants (p.Glu159Lys and p.Phe230Serfs*21) in a POI patient and a homozygous variant (NM_001143764.3: c.271 + 2T > C) in a NOA patient.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 WT1 Jasmine Chew gene: WT1 was added
gene: WT1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: WT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WT1 were set to 26358501; 34845858
Phenotypes for gene: WT1 were set to Primary ovarian failure, MONDO:0005387
Review for gene: WT1 was set to GREEN
Added comment: New papers reported variants associated with POI:
i) PMID: 26358501- Two novel heterozygous missense variants (p. Pro126Ser in exon1 and p. Arg370His in exon7) in two unrelated POI patients, and functional study on these two missense variants showed in impaired transcription of downstream genes, including AMH, FSHR, CYP19 and CDH.

ii) PMID: 34845858- A de novo heterozygous nonsense variant p.R463* in a non-syndromic POI woman. Western blot analysis further demonstrated that the WT1 variant could produce a truncated WT1 isoform in vitro.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 PANX1 Jasmine Chew gene: PANX1 was added
gene: PANX1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PANX1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PANX1 were set to 30918116; 39232764; 35834089; 36469255; 33495594
Phenotypes for gene: PANX1 were set to Oocyte/zygote/embryo maturation arrest 7, MIM# 618550
Review for gene: PANX1 was set to GREEN
Added comment: Literature in OMIM- PMID: 30918116: 4 different monoallelic variants in 4 unrelated Chinese families with 8 women who were infertile due to oocyte death. Functional analysis demonstrated that the mutations alter the PANX1 glycosylation pattern, influence subcellular localization, and increase channel activity and ATP release.

New papers-
i) PMID: 39232764;35834089;36469255- 3 novel monoallelic variants (p.Ser137Leu,p. Arg29Gln, p.Asn326del) causing human oocyte death and female infertility. Western blot analysis confirmed that Arg29Gln and p.Asn326del changed the glycosylation pattern in HeLa cells.

ii) PMID: 33495594- two novel homozygous missense variants associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TRIP13 Jasmine Chew gene: TRIP13 was added
gene: TRIP13 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP13 were set to 32473092; 28553959; 35812326
Phenotypes for gene: TRIP13 were set to Oocyte/zygote/embryo maturation arrest 9, #MIM 619011; Mosaic variegated aneuploidy syndrome 3, #MIM 617598
Review for gene: TRIP13 was set to GREEN
Added comment: Literature in OMIM- PMID: 32473092;28553959- different biallelic variants in >3 unrelated affected individuals

New papers:
i) PMID: 35812326- Two women with zygotic cleavage failure (ZCF) carrying homozygous p. Glu381Lys and compound heterozygous p. Lys420Glu and p. His26Arg. All three variants resulted in obvious changes in hydrogen bonding and consistent increase in DNA damage. Additionally, transcriptomic sequencing of oocytes and arrested embryos containing these variants suggested a greater number of differentially expressed transcripts in germinal vesicle (GV) oocytes than in 1-cell embryos.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 FBXO43 Jasmine Chew gene: FBXO43 was added
gene: FBXO43 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FBXO43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO43 were set to 34052850; 30878252; 34595750
Phenotypes for gene: FBXO43 were set to Oocyte/zygote/embryo maturation arrest 12, MIM# 619697; Spermatogenic failure 64, MIM# 619696
Review for gene: FBXO43 was set to GREEN
Added comment: Literature in OMIM: PMID: 34052850 (three different homozygous variants in 3 unrelated women; 30878252, 34595750 (two different families with different homozygous variants)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 FGA Jasmine Chew gene: FGA was added
gene: FGA was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGA were set to 29016666; 34925444
Phenotypes for gene: FGA were set to Recurrent pregnancy loss
Review for gene: FGA was set to GREEN
Added comment: i) PMID: 29016666- A heterozygous missense p.Phe685Cys called pathogenic in a female with RPL (3 miscarriages, all embryonic loss) and fragment molecular orbital analysis showed that the p.F685C variant led to changes in total interaction energy, thus leading to protein instability

ii) PMID: 34925444: Two heterozygous FGA variants were identified in two women, each with three consecutive miscarriages- one variant (NM_000508.5: c.1906_1908del; p.636del) leading to the deletion of an amino acid was not found in public databases. The other variant in FGA (p.A762V) causing an amino acid substitution was extremely rare in East Asian populations in the gnomAD database and was predicted to be deleterious by in silico prediction tools.
- " Mutations of FGA have been linked to coagulation pathologies including afibrinogenemia (OMIM:202400) and dysfibrinogenemia/hypodysfibrinogenemia (OMIM:616004), which can result in miscarriage (PMID: 31368232).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 KHDC3L Jasmine Chew changed review comment from: Biallelic variants have been reported for several unrelated families with recurrent complete hydatidiform mole (CHM) pregnancy- predominantly biparental and RPL- PMID: 21885028, 19246479, 23232697.

New evidence-
i) PMID 31847873: homozygous LOF variant in a woman with multiple consanguineous marriages in her extended family and history of 2 biparental complete hydatidiform mole (BiCHM) and methylation study on her oocytes revealed a genome-wide deficit of DNA methylation compared with normal human oocytes.

ii) PMID: 31609975- two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and homologous recombination (HR) repair. Also provided functional evidence that KHDC3L dysfunction causes PARP1 inhibition and HR-mediated DNA repair deficiency, which is synthetically lethal.

iii) PMID: 29606347- a novel homozygous frameshift p.Q15Rfs*25 variant in a female patient (II-1) from family 4 with a history of 2 spontaneous abortions and x2 partial hydatidiform moles, and her embryos formed after ICSI are fertilized normally but arrest at the morula stage.
Sources: Literature; to: Biallelic variants have been reported for several unrelated families with recurrent complete hydatidiform mole (CHM) pregnancy- predominantly biparental and RPL- PMID: 21885028, 19246479, 23232697.

New evidence (biallelic variants and CHM pregnancy)-
i) PMID 31847873: homozygous LOF variant in a woman with multiple consanguineous marriages in her extended family and history of 2 biparental complete hydatidiform mole (BiCHM) and methylation study on her oocytes revealed a genome-wide deficit of DNA methylation compared with normal human oocytes.

ii) PMID: 31609975- two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and homologous recombination (HR) repair. Also provided functional evidence that KHDC3L dysfunction causes PARP1 inhibition and HR-mediated DNA repair deficiency, which is synthetically lethal.

iii) PMID: 29606347- a novel homozygous frameshift p.Q15Rfs*25 variant in a female patient (II-1) from family 4 with a history of 2 spontaneous abortions and x2 partial hydatidiform moles, and her embryos formed after ICSI are fertilized normally but arrest at the morula stage.

New evidence (monoallelic variants and RPL)-
i) PMID: 34925444- a heterozygous in frame deletion in KHDC3L (p.146_156del) in a 31-year-old woman with a history of two miscarriages.
ii) PMID: 31609975- heterozygous deletions (p.150_160del and p.150_172del) were found in patients experiencing RPL without forming an hydatidiform mole.
Note: All of the deletions in patients with RPL affected the Thr156 residue, a critical phosphorylation site for normal KHDC3L protein function. Loss of Thr156 results in impaired PARP1 activation and HR repair.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 KHDC3L Jasmine Chew edited their review of gene: KHDC3L: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.63 ZFP36L2 Jasmine Chew gene: ZFP36L2 was added
gene: ZFP36L2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ZFP36L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFP36L2 were set to 34611029; 38829516; 37211617
Phenotypes for gene: ZFP36L2 were set to Oocyte/zygote/embryo maturation arrest 13, MIM# 620154
Review for gene: ZFP36L2 was set to GREEN
Added comment: i) Literature in OMIM- PMID:34611029- x2 unrelated infertile Chinese women with defective oocyte maturation carrying different biallelic variants and functional analysis suggested that the variants cause maternal mRNA decay defects that result in female infertility.

ii) New papers reporting biallelic variants in conjunction with female infertility due to oocyte maturation defect+/- embryonic development arrest
- PMID: 38829516: Novel compound heterozygous variant (p.His62Gln and p.Pro290Leu) in a patient with oocyte maturation defect. These variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes.
- PMID: 37211617: Novel homozygous variant c.853_861del (p.285_287del) in the affected individual with oocyte maturation defect from a consanguineous family. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 REC114 Jasmine Chew gene: REC114 was added
gene: REC114 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: REC114 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REC114 were set to 31704776; 30388401; 38148155
Phenotypes for gene: REC114 were set to Oocyte/zygote/embryo maturation arrest 10, #MIM 619176
Review for gene: REC114 was set to GREEN
Added comment: i) Literature in OMIM (PMID: 31704776;30388401)- x3 unrelated females with different biallelic variants presented with infertility due to oocyte maturation defects/multiple pronuclei zygotes, early embryonic arrest, and failed implantation of surviving embryos/miscarriages/recurrent hydatidiform moles.

ii) New paper on male infertility:
- PMID: 38148155- First report that identifies REC114 as the causative gene for male infertility- homozygous p.Gln190* variant in a Chinese NOA patient. Co-immunoprecipitation (Co-IP) and Western blot (WB) revealed that the variant resulted in truncated REC114 protein and impaired interaction with MEI4, which was essential for meiotic DNA double-strand break (DSB) formation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 WEE2 Jasmine Chew gene: WEE2 was added
gene: WEE2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: WEE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WEE2 were set to 29606300; 30628060; 39476306; 37772619; 36568932; 34476630
Phenotypes for gene: WEE2 were set to Oocyte/zygote/embryo maturation arrest 5, MIM# 617996
Review for gene: WEE2 was set to GREEN
Added comment: i) Literature in OMIM- PMID: 29606300;30628060- >3 unrelated infertile women (e.g., oocyte maturation defect, recurrent fertilization failure) with different biallelic variants

ii) Many other new papers reporting biallelic variants in conjunction with oocyte degradation +/- unexplained fertilization failure - PMID: 39476306;37772619;36568932;34476630

iii) definitive evidence for OZEMA in FeRGI database
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TLE6 Jasmine Chew changed review comment from: i) Literature in OMIM (PMID:26537248)- 3 women from 2 consanguineous Saudi families with primary infertility due to preimplantation embryonic lethality carrying homozygous missense variant, S510Y. ). Functional analysis demonstrated that the variant abrogates TLE6 phosphorylation by PKA and also impairs TLE6 binding to components of the SCMC.

ii) New papers:
- PMID: 31897846- novel biallelic variants (2 homozygous, 1 compound heterozygous) in 3 patients with recurrent IVF/ICSI failure.
- PMID: 40225929- novel compound heterozygous (c.541+2dupT in intron 7 and c.1075G>A) in a female with embryonic developmental arrest (EDA). The splice variant resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. In vitro experiments further validated that the missense variant in NLRP5 led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells.
- PMID: 32172300- A homozygous truncating variant p.(Lys146Glufs*51) in a patient with recurrent pregnancy loss, and demonstrates that oocytes depleted for TLE6 have the capacity to undergo several postfertilization divisions prior to arrest, consistent with what was observed in Tle6-/- mice (Yu et al. 2014)

iii) Classified as definitive for OZEMA in FeRGI database
Sources: Literature; to: i) Literature in OMIM (PMID:26537248)- 3 women from 2 consanguineous Saudi families with primary infertility due to preimplantation embryonic lethality carrying homozygous missense variant, S510Y). Functional analysis demonstrated that the variant abrogates TLE6 phosphorylation by PKA and also impairs TLE6 binding to components of the SCMC.

ii) New papers:
- PMID: 31897846- novel biallelic variants (2 homozygous, 1 compound heterozygous) in 3 patients with recurrent IVF/ICSI failure.
- PMID: 40225929- novel compound heterozygous (c.541+2dupT in intron 7 and c.1075G>A) in a female with embryonic developmental arrest (EDA). The splice variant resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. In vitro experiments further validated that the missense variant in NLRP5 led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells.
- PMID: 32172300- A homozygous truncating variant p.(Lys146Glufs*51) in a patient with recurrent pregnancy loss, and demonstrates that oocytes depleted for TLE6 have the capacity to undergo several postfertilization divisions prior to arrest, consistent with what was observed in Tle6-/- mice (Yu et al. 2014).

iii) Classified as definitive for OZEMA in FeRGI database
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 TLE6 Jasmine Chew gene: TLE6 was added
gene: TLE6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TLE6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TLE6 were set to 26537248; 31897846; 40225929; 32172300
Phenotypes for gene: TLE6 were set to Oocyte/zygote/embryo maturation arrest 15, #MIM 616814
Review for gene: TLE6 was set to GREEN
Added comment: i) Literature in OMIM (PMID:26537248)- 3 women from 2 consanguineous Saudi families with primary infertility due to preimplantation embryonic lethality carrying homozygous missense variant, S510Y. ). Functional analysis demonstrated that the variant abrogates TLE6 phosphorylation by PKA and also impairs TLE6 binding to components of the SCMC.

ii) New papers:
- PMID: 31897846- novel biallelic variants (2 homozygous, 1 compound heterozygous) in 3 patients with recurrent IVF/ICSI failure.
- PMID: 40225929- novel compound heterozygous (c.541+2dupT in intron 7 and c.1075G>A) in a female with embryonic developmental arrest (EDA). The splice variant resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. In vitro experiments further validated that the missense variant in NLRP5 led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells.
- PMID: 32172300- A homozygous truncating variant p.(Lys146Glufs*51) in a patient with recurrent pregnancy loss, and demonstrates that oocytes depleted for TLE6 have the capacity to undergo several postfertilization divisions prior to arrest, consistent with what was observed in Tle6-/- mice (Yu et al. 2014)

iii) Classified as definitive for OZEMA in FeRGI database
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 PABPC1L Jasmine Chew gene: PABPC1L was added
gene: PABPC1L was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PABPC1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PABPC1L were set to 37052235; 37723834; 38177974; 32172300
Phenotypes for gene: PABPC1L were set to Oocyte/zygote/embryo maturation arrest 22, #MIM 621093
Review for gene: PABPC1L was set to GREEN
Added comment: i) Literature in OMIM (PMID: 37052235;37723834;38177974)- >3 unrelated infertile women (due to a mixed phenotype including oocyte maturation abnormalities, fertilization failure, and embryonic development arrest) with different biallelic variants

ii) Additional paper (PMID: 32172300)- Homozygous likely deleterious variant in PABPC1L p.(Met26Lys) in a woman whose infertility phenotype resembles that of Pabpc1l−/− mouse. During her IVF cycles, 18 oocytes were retrieved and subjected to IVF and ICSI. Nine oocytes were assigned to ICSI, but eight were at germinal vesicle stage and only one showed polar body and failed to fertilize following ICSI. Similarly, nine oocytes were assigned to IVF, and only two showed polar body on the next day without any sign of fertilization. The remaining oocytes were at germinal vesicle stage.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 NLRP7 Jasmine Chew gene: NLRP7 was added
gene: NLRP7 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NLRP7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NLRP7 were set to 17579354; 19650864; 25097207; 23201303; 23722513; 32172300; 37148315
Phenotypes for gene: NLRP7 were set to Recurrent hydatidiform mole 1, # MIM 231090
Review for gene: NLRP7 was set to GREEN
Added comment: i) The association between diploid biparental hydatidiform mole (HM), miscarriages, and infertility has been observed in many patients with biallelic functional variants in NLRP7 and some of their HM were diagnosed by morphology as non-molar miscarriages, partial HM (because of their mild trophoblastic proliferation), non-classical HM [PMID: 23201303], or not easy to classify HM [PMID: 23722513].
ii) classified as strong evidence for HM on the FeRGI database
iii) New paper- PMID: 32172300- homozygous truncating variant p.(Lys619Asnfs*18) in an individual with recurrent molar pregnancy and no pregnancy observed following three intra-uterine insemination attempts.
iv) New phenotype (AD):
- PMID: 37148315- five heterozygous variants (c.251G > A, c.1258G > A, c.1441G > A, c. 2227G > A, c.2323C > T) of NLRP7 were identified in five infertile patients who experienced early embryo arrest. Injecting complementary RNAs in mouse oocytes and early embryos showed that NLRP7 variants influenced the oocyte quality and some of the variants significantly affected early embryo development.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 DNAH11 Jasmine Chew gene: DNAH11 was added
gene: DNAH11 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH11 were set to 39256880; 32172300
Phenotypes for gene: DNAH11 were set to Ciliary dyskinesia, primary, 7, with or without situs inversus, # MIM 611884
Added comment: i) PMID: 39256880- Four unrelated asthenoteratozoospermia Chinese males with biallelic deleterious variants in the DNAH11 gene, and 7 of those variants are novel. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated.

ii) PMID: 32172300- One infertile woman with a homozygous truncating variant, p.(Arg3229Trp), presented with primary infertility only. She had three cycles of IVF and had one clinical pregnancy that, unfortunately, ended in a spontaneous loss during first trimester.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.63 ZP3 Zornitza Stark Marked gene: ZP3 as ready
Infertility and Recurrent Pregnancy Loss v0.63 ZP3 Zornitza Stark Gene: zp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.63 ZP3 Zornitza Stark Classified gene: ZP3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.63 ZP3 Zornitza Stark Gene: zp3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.62 ZP2 Zornitza Stark Marked gene: ZP2 as ready
Infertility and Recurrent Pregnancy Loss v0.62 ZP2 Zornitza Stark Gene: zp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.62 ZP2 Zornitza Stark Classified gene: ZP2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.62 ZP2 Zornitza Stark Gene: zp2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.61 ZP1 Zornitza Stark Marked gene: ZP1 as ready
Infertility and Recurrent Pregnancy Loss v0.61 ZP1 Zornitza Stark Gene: zp1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.61 ZP1 Zornitza Stark Classified gene: ZP1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.61 ZP1 Zornitza Stark Gene: zp1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.60 WNT6 Zornitza Stark Marked gene: WNT6 as ready
Infertility and Recurrent Pregnancy Loss v0.60 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.60 WNT6 Zornitza Stark Classified gene: WNT6 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.60 WNT6 Zornitza Stark Gene: wnt6 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.59 WNT6 Zornitza Stark reviewed gene: WNT6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: recurrent pregnancy loss susceptibility, MONDO:0000144; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.59 USP26 Zornitza Stark Marked gene: USP26 as ready
Infertility and Recurrent Pregnancy Loss v0.59 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.59 USP26 Zornitza Stark Classified gene: USP26 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.59 USP26 Zornitza Stark Gene: usp26 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.58 USP26 Zornitza Stark reviewed gene: USP26: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure, X-linked 6, MIM# 301101; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Infertility and Recurrent Pregnancy Loss v0.58 USP26 Zornitza Stark Classified gene: USP26 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.58 USP26 Zornitza Stark Gene: usp26 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.57 UBE2B Zornitza Stark Marked gene: UBE2B as ready
Infertility and Recurrent Pregnancy Loss v0.57 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.57 UBE2B Zornitza Stark Classified gene: UBE2B as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.57 UBE2B Zornitza Stark Gene: ube2b has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.56 TUBB8 Zornitza Stark Marked gene: TUBB8 as ready
Infertility and Recurrent Pregnancy Loss v0.56 TUBB8 Zornitza Stark Gene: tubb8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.56 TUBB8 Zornitza Stark Classified gene: TUBB8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.56 TUBB8 Zornitza Stark Gene: tubb8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.55 TACC3 Zornitza Stark Phenotypes for gene: TACC3 were changed from to Female infertility due to oocyte meiotic arrest, MONDO:0044626
Infertility and Recurrent Pregnancy Loss v0.54 TACC3 Zornitza Stark Marked gene: TACC3 as ready
Infertility and Recurrent Pregnancy Loss v0.54 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.54 TACC3 Zornitza Stark Classified gene: TACC3 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.54 TACC3 Zornitza Stark Gene: tacc3 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.53 TACC3 Zornitza Stark reviewed gene: TACC3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Female infertility due to oocyte meiotic arrest, MONDO:0044626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.53 STAG3 Zornitza Stark Marked gene: STAG3 as ready
Infertility and Recurrent Pregnancy Loss v0.53 STAG3 Zornitza Stark Gene: stag3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.53 STAG3 Zornitza Stark Classified gene: STAG3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.53 STAG3 Zornitza Stark Gene: stag3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.52 STAG3 Zornitza Stark reviewed gene: STAG3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure 8, MIM# 615723, Spermatogenic failure 61, MIM# 619672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.52 SOHLH1 Zornitza Stark Marked gene: SOHLH1 as ready
Infertility and Recurrent Pregnancy Loss v0.52 SOHLH1 Zornitza Stark Gene: sohlh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.52 SOHLH1 Zornitza Stark Classified gene: SOHLH1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.52 SOHLH1 Zornitza Stark Gene: sohlh1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.51 SLC26A8 Zornitza Stark Marked gene: SLC26A8 as ready
Infertility and Recurrent Pregnancy Loss v0.51 SLC26A8 Zornitza Stark Gene: slc26a8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.51 SLC26A8 Zornitza Stark Classified gene: SLC26A8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.51 SLC26A8 Zornitza Stark Gene: slc26a8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.50 PSMC3IP Zornitza Stark Marked gene: PSMC3IP as ready
Infertility and Recurrent Pregnancy Loss v0.50 PSMC3IP Zornitza Stark Gene: psmc3ip has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.50 PSMC3IP Zornitza Stark Classified gene: PSMC3IP as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.50 PSMC3IP Zornitza Stark Gene: psmc3ip has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.49 PRDM9 Zornitza Stark Marked gene: PRDM9 as ready
Infertility and Recurrent Pregnancy Loss v0.49 PRDM9 Zornitza Stark Gene: prdm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.49 PRDM9 Zornitza Stark Classified gene: PRDM9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.49 PRDM9 Zornitza Stark Gene: prdm9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.48 POF1B Zornitza Stark Marked gene: POF1B as ready
Infertility and Recurrent Pregnancy Loss v0.48 POF1B Zornitza Stark Gene: pof1b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.48 POF1B Zornitza Stark edited their review of gene: POF1B: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Infertility and Recurrent Pregnancy Loss v0.48 POF1B Zornitza Stark Classified gene: POF1B as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.48 POF1B Zornitza Stark Gene: pof1b has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.47 POF1B Zornitza Stark reviewed gene: POF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure 2B, MIM# 300604; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.47 PDHA2 Zornitza Stark Marked gene: PDHA2 as ready
Infertility and Recurrent Pregnancy Loss v0.47 PDHA2 Zornitza Stark Gene: pdha2 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.47 PDHA2 Zornitza Stark Classified gene: PDHA2 as Red List (low evidence)
Infertility and Recurrent Pregnancy Loss v0.47 PDHA2 Zornitza Stark Gene: pdha2 has been classified as Red List (Low Evidence).
Infertility and Recurrent Pregnancy Loss v0.46 PDHA2 Zornitza Stark reviewed gene: PDHA2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 70, MIM# 619828; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.46 PATL2 Zornitza Stark Marked gene: PATL2 as ready
Infertility and Recurrent Pregnancy Loss v0.46 PATL2 Zornitza Stark Gene: patl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.46 PATL2 Zornitza Stark Classified gene: PATL2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.46 PATL2 Zornitza Stark Gene: patl2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.45 PADI6 Zornitza Stark Marked gene: PADI6 as ready
Infertility and Recurrent Pregnancy Loss v0.45 PADI6 Zornitza Stark Gene: padi6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.45 PADI6 Zornitza Stark Classified gene: PADI6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.45 PADI6 Zornitza Stark Gene: padi6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.44 NOBOX Zornitza Stark Marked gene: NOBOX as ready
Infertility and Recurrent Pregnancy Loss v0.44 NOBOX Zornitza Stark Gene: nobox has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.44 NOBOX Zornitza Stark Classified gene: NOBOX as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.44 NOBOX Zornitza Stark Gene: nobox has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.43 MSH4 Zornitza Stark Marked gene: MSH4 as ready
Infertility and Recurrent Pregnancy Loss v0.43 MSH4 Zornitza Stark Gene: msh4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.43 MSH4 Zornitza Stark Classified gene: MSH4 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.43 MSH4 Zornitza Stark Gene: msh4 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.42 FSHR Zornitza Stark Marked gene: FSHR as ready
Infertility and Recurrent Pregnancy Loss v0.42 FSHR Zornitza Stark Gene: fshr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.42 FSHR Zornitza Stark Classified gene: FSHR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.42 FSHR Zornitza Stark Gene: fshr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.41 FSHR Zornitza Stark reviewed gene: FSHR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ovarian dysgenesis 1 MONDO:0024463, Ovarian hyperstimulation syndrome MONDO:0011972; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.41 FSHB Zornitza Stark Marked gene: FSHB as ready
Infertility and Recurrent Pregnancy Loss v0.41 FSHB Zornitza Stark Gene: fshb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.41 FSHB Zornitza Stark Classified gene: FSHB as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.41 FSHB Zornitza Stark Gene: fshb has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.40 ELL3 Zornitza Stark Marked gene: ELL3 as ready
Infertility and Recurrent Pregnancy Loss v0.40 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.40 ELL3 Zornitza Stark Phenotypes for gene: ELL3 were changed from to Pregnancy loss, recurrent, susceptibility to, MONDO:0000144, ELL3-related
Infertility and Recurrent Pregnancy Loss v0.39 ELL3 Zornitza Stark Classified gene: ELL3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.39 ELL3 Zornitza Stark Gene: ell3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.38 DNAH8 Zornitza Stark Marked gene: DNAH8 as ready
Infertility and Recurrent Pregnancy Loss v0.38 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.38 DNAH8 Zornitza Stark Classified gene: DNAH8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.38 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.37 DNAH1 Zornitza Stark Marked gene: DNAH1 as ready
Infertility and Recurrent Pregnancy Loss v0.37 DNAH1 Zornitza Stark Gene: dnah1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.37 DNAH1 Zornitza Stark Classified gene: DNAH1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.37 DNAH1 Zornitza Stark Gene: dnah1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.36 DHH Zornitza Stark Marked gene: DHH as ready
Infertility and Recurrent Pregnancy Loss v0.36 DHH Zornitza Stark Gene: dhh has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.36 DHH Zornitza Stark Classified gene: DHH as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.36 DHH Zornitza Stark Gene: dhh has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.35 CPEB1 Zornitza Stark Marked gene: CPEB1 as ready
Infertility and Recurrent Pregnancy Loss v0.35 CPEB1 Zornitza Stark Gene: cpeb1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.35 CPEB1 Zornitza Stark Phenotypes for gene: CPEB1 were changed from Primary ovarian insufficiency, MONDO:0005387 to Primary ovarian insufficiency, MONDO:0005387, CPEB1-related
Infertility and Recurrent Pregnancy Loss v0.34 CPEB1 Zornitza Stark Classified gene: CPEB1 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.34 CPEB1 Zornitza Stark Gene: cpeb1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.33 CPEB1 Zornitza Stark reviewed gene: CPEB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian insufficiency, MONDO:0005387, CPEB1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.33 CPEB1 Zornitza Stark Tag SV/CNV tag was added to gene: CPEB1.
Infertility and Recurrent Pregnancy Loss v0.33 CFTR Zornitza Stark Marked gene: CFTR as ready
Infertility and Recurrent Pregnancy Loss v0.33 CFTR Zornitza Stark Gene: cftr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.33 CFTR Zornitza Stark Classified gene: CFTR as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.33 CFTR Zornitza Stark Gene: cftr has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.32 AMHR2 Zornitza Stark Marked gene: AMHR2 as ready
Infertility and Recurrent Pregnancy Loss v0.32 AMHR2 Zornitza Stark Gene: amhr2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.32 AMHR2 Zornitza Stark Classified gene: AMHR2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.32 AMHR2 Zornitza Stark Gene: amhr2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.31 AMH Zornitza Stark Marked gene: AMH as ready
Infertility and Recurrent Pregnancy Loss v0.31 AMH Zornitza Stark Gene: amh has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.31 AMH Zornitza Stark Classified gene: AMH as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.31 AMH Zornitza Stark Gene: amh has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.30 AARS2 Zornitza Stark Marked gene: AARS2 as ready
Infertility and Recurrent Pregnancy Loss v0.30 AARS2 Zornitza Stark Gene: aars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.30 AARS2 Zornitza Stark Classified gene: AARS2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.30 AARS2 Zornitza Stark Gene: aars2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.29 UBE2B Jasmine Chew changed review comment from: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patient in the Chinese pop, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Literature; to: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): Reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patients in the Chinese population, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 UBE2B Jasmine Chew edited their review of gene: UBE2B: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.29 UBE2B Jasmine Chew changed review comment from: i) PMID: 23378580 (2013)- identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous.

ii) PMID: 26223869 (2015): reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patient in the Chinese pop, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Literature; to: i) PMID: 23378580 (2013)- Identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous. Their findings suggested that two distinct molecular mechanisms, mRNA editing and splicing processing, were disrupted in oligozoospermia.

ii) PMID: 26223869 (2015): reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patient in the Chinese pop, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 UBE2B Jasmine Chew gene: UBE2B was added
gene: UBE2B was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: UBE2B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UBE2B were set to 23378580; 26223869; 12784252
Phenotypes for gene: UBE2B were set to Male infertility, MONDO:0005372
Added comment: i) PMID: 23378580 (2013)- identified nine splicing, four missense and two nonsense alterations in unrelated oligospermic patients, majority are heterozygous, only 3 were homozygous.

ii) PMID: 26223869 (2015): reported four known and novel heterozygous variants in idiopathic azoospermia (IA) patient in the Chinese pop, and one of the missense variant was demonstrated to inhibit the transcriptional regulation activity of SP1 transcription factor, suggesting that it confers a high risk for IA.

iii) PMID: 12784252 (2003)- Ube2b(-/-) mice were shown to present male infertility and their sperm head shape anomalies suggested that Ube2b may be involved in the replacement of nuclear proteins during spermatid chromatin condensation.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 DNAH8 Jasmine Chew gene: DNAH8 was added
gene: DNAH8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH8 were set to 32619401; 32681648; 36308074; 33704367
Phenotypes for gene: DNAH8 were set to Spermatogenic failure 46, MIM# 619095
Review for gene: DNAH8 was set to GREEN
Added comment: Literature in OMIM- PMID: 32619401;32681648- multiple cases with multiple morphologic abnormalities of the sperm flagella (MMAF) carrying biallelic variants

New papers:
i) PMID: 36308074- A novel homozygous frameshift variant in DNAH8 causes MMAF in a consanguineous Pakistani family. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 variant. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Immunofluorescence assay also showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa.

ii) PMID: 33704367- Two unrelated infertile Chinese patients with MMAF carrying different compound heterozygous variants. Immunofluorescence assay showed that DNAH8 protein expression was significantly decreased in the sperm tail of the patients, and electron microscopy exhibited an abnormal flagellum ultrastructure, while clinical pregnancy could be achieved by intracytoplasmic sperm injection.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 DNAH1 Jasmine Chew changed review comment from: Literature in OMIM- PMID: 24360805, 27798045, 27573432, 28552195, 28577616, 29449551- multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF)
Sources: Literature; to: Literature in OMIM- PMID: 24360805, 27798045, 27573432, 28552195, 28577616, 29449551- multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF) carrying biallelic variants
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 DNAH1 Jasmine Chew gene: DNAH1 was added
gene: DNAH1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DNAH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH1 were set to 24360805; 27798045; 27573432; 28552195; 28577616; 29449551
Phenotypes for gene: DNAH1 were set to Spermatogenic failure 18 , MIM# 617576
Review for gene: DNAH1 was set to GREEN
Added comment: Literature in OMIM- PMID: 24360805, 27798045, 27573432, 28552195, 28577616, 29449551- multiple unrelated cases with multiple morphological abnormalities of the sperm flagella (MMAF)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 DHH Jasmine Chew gene: DHH was added
gene: DHH was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHH were set to 25927242; 28589169; 28708305; 29471294; 40176231
Phenotypes for gene: DHH were set to 46XY gonadal dysgenesis with minifascicular neuropathy, MIM# 607080
Review for gene: DHH was set to GREEN
Added comment: Literature in OMIM- PubMed: 25927242; 28589169; 28708305; 29471294- biallelic variants in affected women with primary amenorrhea, also one woman from PMID:29471294 had 2 uneventful pregnancies.

New paper:
PMID: 40176231-novel homozygous missense variant (P. Ser185Pro) in an Indian female with primary amenorrhea and severe motor and sensory neuropathy with Charcot's joints.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 CPEB1 Jasmine Chew changed review comment from: i) PMID: 32354341 (2020)- heterozygous deletion of exons 8-12 in a Chinese patient with primary amenorrhea.

ii) PMID: 33095795 (2020)- heterozygous 83.8-kb deletion (in the similar region reported previously) and a heterozygous missense variant (p.R87C) reported in two Brazilian female with POI (POI-4, POI-14).

iii) PMID: 27003306 (2016)- identified three POI patients carrying overlapping microdeletions disrupting CPEB1, which is the only gene known to be involved in reproduction in the deleted regions. Also suggested given that CEPB1 is located in a chromosomal region containing LCRs, the involvement of this gene in POI can be hypothesized to be related to microdeletions in the 15q25.2 region rather than to CPEB1 variants.

iv) PMID: 21256485 (2011)- POF-87 with novel heterozygous microdeletion including CPEB1 (1.67 Mb del including the entire CPEB1).
Sources: Literature; to: i) PMID: 32354341 (2020)- heterozygous deletion of exons 8-12 in a Chinese patient with primary amenorrhea.

ii) PMID: 33095795 (2020)- heterozygous 83.8-kb deletion (in the similar region reported previously) and a heterozygous missense variant (p.R87C) reported in two Brazilian female with POI (POI-4, POI-14).

iii) PMID: 27003306 (2016)- identified three POI patients carrying overlapping microdeletions disrupting CPEB1, which is the only gene known to be involved in reproduction in the deleted regions. Also suggested given that CEPB1 is located in a chromosomal region containing LCRs, the involvement of this gene in POI can be hypothesized to be related to microdeletions in the 15q25.2 region rather than to CPEB1 variants.

iv) PMID: 21256485 (2011)- POF-87 with novel heterozygous microdeletion including CPEB1 (1.67 Mb del including the entire CPEB1).

Note: CPEB1 dosage sensitivity curation pending review
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 CPEB1 Jasmine Chew gene: CPEB1 was added
gene: CPEB1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CPEB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CPEB1 were set to 21256485; 27003306; 33095795; 32354341
Phenotypes for gene: CPEB1 were set to Primary ovarian insufficiency, MONDO:0005387
Review for gene: CPEB1 was set to GREEN
Added comment: i) PMID: 32354341 (2020)- heterozygous deletion of exons 8-12 in a Chinese patient with primary amenorrhea.

ii) PMID: 33095795 (2020)- heterozygous 83.8-kb deletion (in the similar region reported previously) and a heterozygous missense variant (p.R87C) reported in two Brazilian female with POI (POI-4, POI-14).

iii) PMID: 27003306 (2016)- identified three POI patients carrying overlapping microdeletions disrupting CPEB1, which is the only gene known to be involved in reproduction in the deleted regions. Also suggested given that CEPB1 is located in a chromosomal region containing LCRs, the involvement of this gene in POI can be hypothesized to be related to microdeletions in the 15q25.2 region rather than to CPEB1 variants.

iv) PMID: 21256485 (2011)- POF-87 with novel heterozygous microdeletion including CPEB1 (1.67 Mb del including the entire CPEB1).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 CFTR Jasmine Chew gene: CFTR was added
gene: CFTR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CFTR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFTR were set to 30214069; 40169970; 39592508; 39356031
Phenotypes for gene: CFTR were set to Congenital bilateral absence of vas deferens, MIM# 277180
Review for gene: CFTR was set to GREEN
Added comment: OMIM- Found in more than 25% of men with obstructive azoospermia, involving a complete or partial defect of the Wolffian duct derivatives; PMID: 30214069

New case reports- PMID: 40169970; 39592508; 39356031
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 AMHR2 Jasmine Chew gene: AMHR2 was added
gene: AMHR2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AMHR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMHR2 were set to 7493017; 8872466; 19457927; 35052499; 33025551; 34480531
Phenotypes for gene: AMHR2 were set to Persistent Mullerian duct syndrome, type I, MIM #261550
Review for gene: AMHR2 was set to GREEN
Added comment: Literature in OMIM- PMID: 7493017; 8872466;19457927

New papers:
i) PMID: 35052499- compound heterozygous variants in case 2 and case 3 with azoospermia/oligospermia.

ii) PMID: 33025551- seven different variants identified in 11 cases from six unrelated Turkish families with PMDS (didn't mention if they were infertile).

iii) PMID: 34480531- compound heterozygous variants of c.1387C>T (p.R463C) and c.1219C>T (p.R407X) in exons 9 and 10, respectively, in two brothers who had a history of bilateral cryptorchidism with orchidopexy as well as infertility due to azoospermia.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 AMH Jasmine Chew changed review comment from: Literature in OMIM- PMID: 2023927;1483695;11760020

New papers:
i) PMID: 39889328 - novel homozygous missense p.Pro550Leu in a Tuscinian man with primary infertilitydue to Persistent Müllerian duct syndrome and biopsy revealed no spermatozoa

ii) PMID: 35052499- homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 in case 1 with non-obstructive azoospermia, leading to the loss of function of AMH.
; to: Literature in OMIM- PMID: 2023927;1483695;11760020

New papers:
i) PMID: 39889328 - novel homozygous missense p.Pro550Leu in a Tuscinian man with primary infertility due to Persistent Müllerian duct syndrome and biopsy revealed no spermatozoa.

ii) PMID: 35052499- homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 in case 1 with non-obstructive azoospermia, leading to the loss of function of AMH.
Infertility and Recurrent Pregnancy Loss v0.29 AMH Jasmine Chew changed review comment from: Literature in OMIM- PMID: 2023927;1483695;11760020

New papers:
i) PMID: 39889328 - novel homozygous missense p.Pro550Leu in a Tuscinian man with primary infertilitydue to Persistent Müllerian duct syndrome and biopsy revealed no spermatozoa

ii) PMID: 35052499- case 1 with non-obstructive azoospermia carrying homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 of AMH, leading to the loss of function of AMH.
Sources: Literature; to: Literature in OMIM- PMID: 2023927;1483695;11760020

New papers:
i) PMID: 39889328 - novel homozygous missense p.Pro550Leu in a Tuscinian man with primary infertilitydue to Persistent Müllerian duct syndrome and biopsy revealed no spermatozoa

ii) PMID: 35052499- homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 in case 1 with non-obstructive azoospermia, leading to the loss of function of AMH.
Infertility and Recurrent Pregnancy Loss v0.29 AMH Jasmine Chew gene: AMH was added
gene: AMH was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AMH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMH were set to 2023927; 1483695; 11760020; 39889328; 35052499
Phenotypes for gene: AMH were set to Persistent Mullerian duct syndrome, type I, MIM# 261550
Review for gene: AMH was set to GREEN
Added comment: Literature in OMIM- PMID: 2023927;1483695;11760020

New papers:
i) PMID: 39889328 - novel homozygous missense p.Pro550Leu in a Tuscinian man with primary infertilitydue to Persistent Müllerian duct syndrome and biopsy revealed no spermatozoa

ii) PMID: 35052499- case 1 with non-obstructive azoospermia carrying homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 of AMH, leading to the loss of function of AMH.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 AARS2 Jasmine Chew edited their review of gene: AARS2: Changed phenotypes: Progressive leukoencephalopathy with ovarian failure, MIM# 615889
Infertility and Recurrent Pregnancy Loss v0.29 AARS2 Jasmine Chew gene: AARS2 was added
gene: AARS2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS2 were set to 24808023; 32775515; 31280959; 29749055
Phenotypes for gene: AARS2 were set to Leukoencephalopathy, progressive, with ovarian failure, MIM# 615889
Review for gene: AARS2 was set to GREEN
Added comment: Literature in OMIM- PMID:24808023- compound heterozygous missense variants in 5 women with premature ovarian failure among 6 with progressive leukoencephalopathy, and studies of the yeast homologs of 2 variants (F50C and R521X) showed that they resulted in a complete or partial loss of protein function.

New papers- case reports of biallelic variants in patients with POIPOF
- PMID:32775515; 31280959; 29749055
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 STAG3 Jasmine Chew gene: STAG3 was added
gene: STAG3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: STAG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAG3 were set to 24597867; 26059840; 28393351; 30006057; 32634216; 31125047; 31682730
Phenotypes for gene: STAG3 were set to Premature ovarian failure 8, MIM# 615723; Spermatogenic failure 61, MIM# 619672
Added comment: Literature in OMIM (PMID:24597867; 26059840; 28393351;30006057;32634216; 31125047; 31682730)- biallelic missense and LOF variants reported in conjunction with primary ovarian failure and spermatogenic failure

New papers reporting biallelic LOF variants for POI- PMID: 34497033; 35503298

New papers reporting biallelic LOF variants for NOA- PMID: 33980954

New papers reporting biallelic LOF variants for both POI and NOA in familial cases- PMID: 39932630; 35176428
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 ZP2 Jasmine Chew edited their review of gene: ZP2: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.29 MSH4 Jasmine Chew gene: MSH4 was added
gene: MSH4 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MSH4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH4 were set to 28541421; 33448284; 34755185; 33437391; 33448284; 35090489; 34755185; 38175272; 37620942
Phenotypes for gene: MSH4 were set to Premature ovarian failure 20, MIM# 619938; Spermatogenic failure 2, MIM# 108420
Review for gene: MSH4 was set to GREEN
Added comment: Literature in OMIM (PMID:28541421;33448284; 34755185;33437391;33448284; 35090489; 34755185)- biallelic LOF and missense variants reported in multiple familial cases with premature ovarian failure and spermatogenic failure/azoospermia

New papers:
i) PMID: 38175272- novel homozygous nonsense variant ( p.Q40*) in an Iranian family with four affected members consisting of two NOA men with maturation arrest and two women with POI. This variant occurs at the beginning of MSH4 and leads to the formation of a very short chain with 39 residues or complete loss of protein, which it is likely the main reason for the emergence of POI and NOA. Testicular sperm retrieval and ovarian stimulation cycles have not been successful in any of patients.

ii) PMID: 37620942- compound heterozygous variants (p.Thr792Ala and p.Lys741Argfs*2) in a woman with diminished ovarian reserve (DOR), presented with poor oocyte quantity and quality, resulting in unsuccessful in vitro fertilization cycles. Bioinformatics and in vitro functional analysis showed that the p.Thr792Ala variant altered the local conformation of the MutS_V domain without decreasing MSH4 protein expression, while the p.Lys741Argfs*2 variant led to a reduction in MSH4 protein expression without impacting splicing.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 FSHB Jasmine Chew edited their review of gene: FSHB: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.29 FSHB Jasmine Chew gene: FSHB was added
gene: FSHB was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FSHB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSHB were set to 8220432; 8220432; 9624193; 9806482; 12161499
Phenotypes for gene: FSHB were set to Hypogonadotropic hypogonadism 24 without anosmia, MIM# 229070
Added comment: Literature in OMIM (PMID:8220432;8220432;9624193;9806482;12161499)- multiple unrelated infertile women and males with isolated FSH deficiency carrying biallelic LOF variants
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 FSHR Jasmine Chew gene: FSHR was added
gene: FSHR was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FSHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FSHR were set to 7553856; 9769327; 11889179; 20087398; 12930927; 12930928; 17721928; 36704038
Phenotypes for gene: FSHR were set to Ovarian dysgenesis 1, MIM# 233300; Ovarian hyperstimulation syndrome, MIM# 608115
Added comment: Literature in OMIM-
i) biallelic variants for ovarian dysgenesis, supported by functional evidence- PMID:7553856; 9769327;11889179;20087398
ii) monoallelic variants for ovarian hyperstimulation syndrome- PMID:12930927;12930928;17721928

New paper:
i) PMID: 36704038- Novel compound heterozygous variants (Ala462Pro and p.Ala621Val) in a woman with primary ovarian insufficiency with resistant ovary syndrome. In vitro experiments revealed that the p.Ala462Pro variant resulted in barely detectable levels of intracellular signaling both in cAMP-dependent CRE-reporter activity and ERK activation and displayed a severely reduced plasma membrane receptor expression. In contrast, the p.Ala621Val variant resulted in partial loss of receptor activation without disruption of cell surface expression.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.29 NLRP5 Zornitza Stark Marked gene: NLRP5 as ready
Infertility and Recurrent Pregnancy Loss v0.29 NLRP5 Zornitza Stark Gene: nlrp5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.29 NLRP5 Zornitza Stark Classified gene: NLRP5 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.29 NLRP5 Zornitza Stark Gene: nlrp5 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.28 HFM1 Zornitza Stark Marked gene: HFM1 as ready
Infertility and Recurrent Pregnancy Loss v0.28 HFM1 Zornitza Stark Gene: hfm1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.28 HFM1 Zornitza Stark Classified gene: HFM1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.28 HFM1 Zornitza Stark Gene: hfm1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.27 GDF9 Zornitza Stark Marked gene: GDF9 as ready
Infertility and Recurrent Pregnancy Loss v0.27 GDF9 Zornitza Stark Gene: gdf9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.27 GDF9 Zornitza Stark Classified gene: GDF9 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.27 GDF9 Zornitza Stark Gene: gdf9 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.26 KHDC3L Zornitza Stark Marked gene: KHDC3L as ready
Infertility and Recurrent Pregnancy Loss v0.26 KHDC3L Zornitza Stark Gene: khdc3l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.26 KHDC3L Zornitza Stark Classified gene: KHDC3L as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.26 KHDC3L Zornitza Stark Gene: khdc3l has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.25 GDF9 Jasmine Chew gene: GDF9 was added
gene: GDF9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GDF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDF9 were set to 29044499; 33036707; 38643161
Phenotypes for gene: GDF9 were set to Premature ovarian failure 14, MIM# 618014
Review for gene: GDF9 was set to GREEN
Added comment: Literature in OMIM- PMID:29044499;33036707 - biallelic variants reported in women with premature ovarian failure, supported by functional evidence

New paper:
i) PMID: 38643161 (2024)- compound heterozygous variants (Q321X/S428T) in two infertile women with defect in follicle enlargement In vitro experiments confirmed that these variants caused reduction of GDF9 secretion, and/or alleviation in BMP15 binding. Moreover, Q308X/S415T mouse model was constructed, which recapitulated the phenotypes in probands with abnormal estrogen secretion and defected follicle enlargement. n addition, RNA sequencing of granulosa cells revealed the transcriptomic profiles related to defective follicle enlargement in theQ308X/S415T group.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.25 HFM1 Jasmine Chew changed review comment from: Literature in OMIM- PMID:24597873- compound heterozygous variants in a familial case and an unrelated individual with primary ovarian failure

New papers (single family with monoallelic variant and expansion of phenotypes in females)
i) PMID: 31279343- Novel heterozygous missense variant in HFM1 (c.3470G > A) in the proband and her mother both affected by POI. Minigene splicing assay of the WT and MT constructs revealed that an alternative splicing process were produced with the c.3470G > A variant in mRNA level.

ii) PMID: 35881270- novel compound heterozygous variants,c.1978-2A > C and c.2680 + 3_2680 + 4delAT, in two sisters with diminished ovarian reserve and recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Minigene assay showed that both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. These results demonstrated that RPL caused by the HFM1 gene might be inherited in AR mode,

iii) PMID: 36864181- novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings - female with poor ovarian response and recurrent implantation failure and male with NOA. Minigene assay demonstrated that splicing variants caused abnormal alternative splicing of HFM1. For the sister, she experienced embryo arrest 9 weeks after pregnancy after undergoing 5 cycles of ART.

iv) PMID: 39929154- reported compound heterozygous variants c.1978-2A>C and c.2681-3T>A in a case of POI with unique genital characteristics; also their lit review showed that previous studies have linked HFM1 gene variants to clinical manifestations such as POI, diminished ovarian reserve, recurrent pregnancy loss, and poor outcomes in in vitro fertilization-embryo transfer.
Sources: Literature; to: Literature in OMIM- PMID:24597873- compound heterozygous variants in a familial case and an unrelated individual with primary ovarian failure

New papers (single family with monoallelic variant and expansion of phenotypes in females)
i) PMID: 31279343- Novel heterozygous missense variant in HFM1 (c.3470G > A) in the proband and her mother both affected by POI. Minigene splicing assay of the WT and MT constructs revealed that an alternative splicing process were produced with the c.3470G > A variant in mRNA level.

ii) PMID: 35881270- novel compound heterozygous variants,c.1978-2A > C and c.2680 + 3_2680 + 4delAT, in two sisters with diminished ovarian reserve and recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Minigene assay showed that both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. These results demonstrated that RPL caused by the HFM1 gene might be inherited in AR mode,

iii) PMID: 36864181- novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings - female with poor ovarian response and recurrent implantation failure and male with NOA. Minigene assay demonstrated that splicing variants caused abnormal alternative splicing of HFM1. For the sister, she experienced embryo arrest 9 weeks after pregnancy after undergoing 5 cycles of ART.

iv) PMID: 39929154- reported compound heterozygous variants c.1978-2A>C and c.2681-3T>A in a case of POI with unique genital characteristics; also their lit review showed that previous studies have linked HFM1 gene variants to clinical manifestations such as POI, diminished ovarian reserve, recurrent pregnancy loss, and poor outcomes in in vitro fertilization-embryo transfer.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.25 HFM1 Jasmine Chew changed review comment from: Literature in OMIM- PMID:24597873- compound heterozygous variants in a familial case and an unrelated individual with primary ovarian failure

New papers (single family with monoallelic variant and expansion of phenotypes)
i) PMID: 31279343- Novel heterozygous missense variant in HFM1 (c.3470G > A) in the proband and her mother both affected by POI. Minigene splicing assay of the WT and MT constructs revealed that an alternative splicing process were produced with the c.3470G > A variant in mRNA level.

ii) PMID: 35881270- novel compound heterozygous variants,c.1978-2A > C and c.2680 + 3_2680 + 4delAT, in two sisters with diminished ovarian reserve and recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Minigene assay showed that both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. These results demonstrated that RPL caused by the HFM1 gene might be inherited in AR mode,

iii) PMID: 36864181 (2023)- novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings - female with poor ovarian response and recurrent implantation failure and male with NOA. Minigene assay demonstrated that splicing variants caused abnormal alternative splicing of HFM1. For the sister, she experienced embryo arrest 9 weeks after pregnancy after undergoing 5 cycles of ART.

iv) PMID: 39929154 (2025)- reported compound heterozygous variants c.1978-2A>C and c.2681-3T>A in a case of POI with unique genital characteristics; also their lit review showed that previous studies have linked HFM1 gene variants to clinical manifestations such as POI, diminished ovarian reserve, recurrent pregnancy loss, and poor outcomes in in vitro fertilization-embryo transfer.
Sources: Literature; to: Literature in OMIM- PMID:24597873- compound heterozygous variants in a familial case and an unrelated individual with primary ovarian failure

New papers (single family with monoallelic variant and expansion of phenotypes in females)
i) PMID: 31279343- Novel heterozygous missense variant in HFM1 (c.3470G > A) in the proband and her mother both affected by POI. Minigene splicing assay of the WT and MT constructs revealed that an alternative splicing process were produced with the c.3470G > A variant in mRNA level.

ii) PMID: 35881270- novel compound heterozygous variants,c.1978-2A > C and c.2680 + 3_2680 + 4delAT, in two sisters with diminished ovarian reserve and recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Minigene assay showed that both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. These results demonstrated that RPL caused by the HFM1 gene might be inherited in AR mode,

iii) PMID: 36864181- novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings - female with poor ovarian response and recurrent implantation failure and male with NOA. Minigene assay demonstrated that splicing variants caused abnormal alternative splicing of HFM1. For the sister, she experienced embryo arrest 9 weeks after pregnancy after undergoing 5 cycles of ART.

iv) PMID: 39929154- reported compound heterozygous variants c.1978-2A>C and c.2681-3T>A in a case of POI with unique genital characteristics; also their lit review showed that previous studies have linked HFM1 gene variants to clinical manifestations such as POI, diminished ovarian reserve, recurrent pregnancy loss, and poor outcomes in in vitro fertilization-embryo transfer.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.25 HFM1 Jasmine Chew gene: HFM1 was added
gene: HFM1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: HFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HFM1 were set to 24597873; 31279343; 35881270; 36864181; 39929154
Phenotypes for gene: HFM1 were set to Premature ovarian failure 9, MIM# 615724
Review for gene: HFM1 was set to GREEN
Added comment: Literature in OMIM- PMID:24597873- compound heterozygous variants in a familial case and an unrelated individual with primary ovarian failure

New papers (single family with monoallelic variant and expansion of phenotypes)
i) PMID: 31279343- Novel heterozygous missense variant in HFM1 (c.3470G > A) in the proband and her mother both affected by POI. Minigene splicing assay of the WT and MT constructs revealed that an alternative splicing process were produced with the c.3470G > A variant in mRNA level.

ii) PMID: 35881270- novel compound heterozygous variants,c.1978-2A > C and c.2680 + 3_2680 + 4delAT, in two sisters with diminished ovarian reserve and recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Minigene assay showed that both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. These results demonstrated that RPL caused by the HFM1 gene might be inherited in AR mode,

iii) PMID: 36864181 (2023)- novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings - female with poor ovarian response and recurrent implantation failure and male with NOA. Minigene assay demonstrated that splicing variants caused abnormal alternative splicing of HFM1. For the sister, she experienced embryo arrest 9 weeks after pregnancy after undergoing 5 cycles of ART.

iv) PMID: 39929154 (2025)- reported compound heterozygous variants c.1978-2A>C and c.2681-3T>A in a case of POI with unique genital characteristics; also their lit review showed that previous studies have linked HFM1 gene variants to clinical manifestations such as POI, diminished ovarian reserve, recurrent pregnancy loss, and poor outcomes in in vitro fertilization-embryo transfer.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.25 MCM8 Zornitza Stark Marked gene: MCM8 as ready
Infertility and Recurrent Pregnancy Loss v0.25 MCM8 Zornitza Stark Gene: mcm8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.25 MCM8 Zornitza Stark Classified gene: MCM8 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.25 MCM8 Zornitza Stark Gene: mcm8 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.24 GGN Zornitza Stark Marked gene: GGN as ready
Infertility and Recurrent Pregnancy Loss v0.24 GGN Zornitza Stark Gene: ggn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.24 GGN Zornitza Stark Mode of pathogenicity for gene: GGN was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Infertility and Recurrent Pregnancy Loss v0.23 GGN Zornitza Stark Classified gene: GGN as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.23 GGN Zornitza Stark Gene: ggn has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.22 FKBP6 Zornitza Stark Marked gene: FKBP6 as ready
Infertility and Recurrent Pregnancy Loss v0.22 FKBP6 Zornitza Stark Gene: fkbp6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.22 FKBP6 Zornitza Stark Classified gene: FKBP6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.22 FKBP6 Zornitza Stark Gene: fkbp6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.21 EIF4ENIF1 Zornitza Stark Marked gene: EIF4ENIF1 as ready
Infertility and Recurrent Pregnancy Loss v0.21 EIF4ENIF1 Zornitza Stark Gene: eif4enif1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.21 EIF4ENIF1 Zornitza Stark Classified gene: EIF4ENIF1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.21 EIF4ENIF1 Zornitza Stark Gene: eif4enif1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.20 DPY19L2 Zornitza Stark Marked gene: DPY19L2 as ready
Infertility and Recurrent Pregnancy Loss v0.20 DPY19L2 Zornitza Stark Gene: dpy19l2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.20 DPY19L2 Zornitza Stark Classified gene: DPY19L2 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.20 DPY19L2 Zornitza Stark Gene: dpy19l2 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.19 MCM8 Jasmine Chew edited their review of gene: MCM8: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.19 BMP15 Zornitza Stark Marked gene: BMP15 as ready
Infertility and Recurrent Pregnancy Loss v0.19 BMP15 Zornitza Stark Gene: bmp15 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.19 BMP15 Zornitza Stark Classified gene: BMP15 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.19 BMP15 Zornitza Stark Gene: bmp15 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.18 MCM8 Jasmine Chew gene: MCM8 was added
gene: MCM8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: MCM8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM8 were set to 25437880; 25873734; 40064807; 32048466
Phenotypes for gene: MCM8 were set to Premature ovarian failure 10, MIM# 612885; Azoospermia, MONDO:0100459
Added comment: Literature in OMIM- PMID:25437880;25873734- homozygous variants reported in affected females with premature ovarian failure, supported by functional evidence

New papers:
i) PMID: 40064807- A novel homozygous frameshift variant (p. Gly333Glufs*50) in two siblings diagnosed with primary gonadal dysgenesis from a consanguineous family. The testes tissue sections in the male showed a Sertoli cell-only syndrome (SCOS). Functional analysis in vitro suggested that the mutation results in a truncated protein of MCM8 in HEK293T cells, and immunohistochemistry in vivo showed decreased expression of MCM8 protein. This study expands the mutational spectrum of MCM8 involved in male NOA and female POI.

ii) PMID: 32048466- A novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.18 AURKC Zornitza Stark Marked gene: AURKC as ready
Infertility and Recurrent Pregnancy Loss v0.18 AURKC Zornitza Stark Gene: aurkc has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.18 AURKC Zornitza Stark Classified gene: AURKC as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.18 AURKC Zornitza Stark Gene: aurkc has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.17 NOBOX Jasmine Chew changed review comment from: Literature in OMIM- PMIM:17701902;21837770;25514101- heterozygous missense and LOF variants reported in affected women with primary ovarian insufficiency, supported by functional evidence

New papers (expansion of phenotypes and novel biallelic variants reported in POI patients)-
i. PMID: 39871066- A heterozygous missense variant (p.His617Tyr) in two European women with distinct distinct oocyte, zygote, and embryo maturation arrest (OZEMA) phenotype. The same variant has been observed in other two woman experiencing embryonic developmental arrest from the database of Juno Genetics. Given that all affected women have a normal to high ovarian reserve, a typical POI phenotype can be excluded in these cases.

ii. PMID: 34480423- novel compound heterozygous truncating variants (p.Arg276Ter and p.Gly474AlafsTer76) in a Belgian patient presenting POI

iii. PMID: 29067606- novel homozygous c.1489delT variant in two sisters with POI
Sources: Literature; to: Literature in OMIM- PMIM:17701902;21837770;25514101- heterozygous missense and LOF variants reported in affected women with primary ovarian insufficiency, supported by functional evidence

New papers (expansion of phenotypes and novel biallelic variants reported in POI patients)-
i. PMID: 39871066- A heterozygous missense variant (p.His617Tyr) in two European women with distinct distinct oocyte, zygote, and embryo maturation arrest (OZEMA) phenotype. The same variant has been observed in other two woman experiencing embryonic developmental arrest from the database of Juno Genetics. Given that all affected women have a normal to high ovarian reserve, a typical POI phenotype can be excluded in these cases.

ii. PMID: 34480423- Novel compound heterozygous truncating variants (p.Arg276Ter and p.Gly474AlafsTer76) in a Belgian patient presenting POI.

iii. PMID: 29067606- a novel homozygous c.1489delT variant in two sisters with POI
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 NOBOX Jasmine Chew gene: NOBOX was added
gene: NOBOX was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NOBOX was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NOBOX were set to 17701902; 21837770; 25514101; 39871066; 34480423; 29067606
Phenotypes for gene: NOBOX were set to Premature ovarian failure 5, MIM# 611548
Review for gene: NOBOX was set to GREEN
Added comment: Literature in OMIM- PMIM:17701902;21837770;25514101- heterozygous missense and LOF variants reported in affected women with primary ovarian insufficiency, supported by functional evidence

New papers (expansion of phenotypes and novel biallelic variants reported in POI patients)-
i. PMID: 39871066- A heterozygous missense variant (p.His617Tyr) in two European women with distinct distinct oocyte, zygote, and embryo maturation arrest (OZEMA) phenotype. The same variant has been observed in other two woman experiencing embryonic developmental arrest from the database of Juno Genetics. Given that all affected women have a normal to high ovarian reserve, a typical POI phenotype can be excluded in these cases.

ii. PMID: 34480423- novel compound heterozygous truncating variants (p.Arg276Ter and p.Gly474AlafsTer76) in a Belgian patient presenting POI

iii. PMID: 29067606- novel homozygous c.1489delT variant in two sisters with POI
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 PATL2 Jasmine Chew changed review comment from: Literature in OMIM- PMID:28965844;28965849; 35091966- biallelic variants in affected women with infertility due to oocyte maturation arrest

New papers-
i) PMID: 32048119- two novel homozygous missense variants (p.Pro510Thr and p.Ser459Tyr) in three patients from two consanguineous families with female infertility due to oocyte maturation arrest. Western immunoblotting analysis showed that the expression levels of the two novel mutant PATL2 proteins decreased significantly.

ii) PMID: 30765866- four novel homozygous missense variants (p.V260M, p.Q300*, p.T425P, and p.D293Y), a novel frameshift variant (p.N239Tfs*9), and a reported splicing mutation (p.R75Vfs*21) in PATL2 in seven affected individuals from five unrelated families, showing a multiplicity of phenotypes in oocyte maturation arrest, fertilization failure, or embryonic developmental arrest.

iii) PMID: 39476306- novel compound heterozygous splicing variant (c.516-1G > T and c.877-1G > A) in a woman with oocyte degeneration and fertilization failure. Minigene splicing assays revealed that the c.516-1G > T resulted in a deletion of 8 bases in mRNA that causes a frameshift (p.P173Q fs*13) and the c.877-1G > A led to the skipping of exons 10 and 11 and retention of introns 8-9 in PATL2 mRNA.

iv) PMID: 38536595- 15 novel biallelic variants in 18 families with impaired oocyte maturation, fertilization problems, embryonic arrest, or implantation failure
Sources: Literature; to: Literature in OMIM- PMID:28965844;28965849; 35091966- biallelic variants in affected women with infertility due to oocyte maturation arrest

New papers-
i) PMID: 32048119- two novel homozygous missense variants (p.Pro510Thr and p.Ser459Tyr) in three patients from two consanguineous families with female infertility due to oocyte maturation arrest. Western immunoblotting analysis showed that the expression levels of the two novel mutant PATL2 proteins decreased significantly.

ii) PMID: 30765866- four novel homozygous missense variants (p.V260M, p.Q300*, p.T425P, and p.D293Y), a novel frameshift variant (p.N239Tfs*9), and a reported splicing mutation (p.R75Vfs*21) in PATL2 in seven affected individuals from five unrelated families, showing a multiplicity of phenotypes in oocyte maturation arrest, fertilization failure, or embryonic developmental arrest.

iii) PMID: 39476306- novel compound heterozygous splicing variant (c.516-1G > T and c.877-1G > A) in a woman with oocyte degeneration and fertilization failure. Minigene splicing assays revealed that the c.516-1G > T resulted in a deletion of 8 bases in mRNA that causes a frameshift (p.P173Q fs*13) and the c.877-1G > A led to the skipping of exons 10 and 11 and retention of introns 8-9 in PATL2 mRNA.

iv) PMID: 38536595- 15 novel biallelic variants in 18 families with infertile women with IVF/ICSI failure due to impaired oocyte maturation, fertilization problems, embryonic arrest, or implantation failure.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 PATL2 Jasmine Chew gene: PATL2 was added
gene: PATL2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PATL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PATL2 were set to 28965844; 28965849; 35091966; 32048119; 30765866; 39476306; 38536595
Phenotypes for gene: PATL2 were set to Oocyte maturation defect 4, MIM# 617743
Review for gene: PATL2 was set to GREEN
Added comment: Literature in OMIM- PMID:28965844;28965849; 35091966- biallelic variants in affected women with infertility due to oocyte maturation arrest

New papers-
i) PMID: 32048119- two novel homozygous missense variants (p.Pro510Thr and p.Ser459Tyr) in three patients from two consanguineous families with female infertility due to oocyte maturation arrest. Western immunoblotting analysis showed that the expression levels of the two novel mutant PATL2 proteins decreased significantly.

ii) PMID: 30765866- four novel homozygous missense variants (p.V260M, p.Q300*, p.T425P, and p.D293Y), a novel frameshift variant (p.N239Tfs*9), and a reported splicing mutation (p.R75Vfs*21) in PATL2 in seven affected individuals from five unrelated families, showing a multiplicity of phenotypes in oocyte maturation arrest, fertilization failure, or embryonic developmental arrest.

iii) PMID: 39476306- novel compound heterozygous splicing variant (c.516-1G > T and c.877-1G > A) in a woman with oocyte degeneration and fertilization failure. Minigene splicing assays revealed that the c.516-1G > T resulted in a deletion of 8 bases in mRNA that causes a frameshift (p.P173Q fs*13) and the c.877-1G > A led to the skipping of exons 10 and 11 and retention of introns 8-9 in PATL2 mRNA.

iv) PMID: 38536595- 15 novel biallelic variants in 18 families with impaired oocyte maturation, fertilization problems, embryonic arrest, or implantation failure
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 POF1B Jasmine Chew changed review comment from: Literature in OMIM- PMID:16773570- familial case with POF carrying homozygous R329Q, supported by functional evidence.

New papers:
i) PMID: 25676666- reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense variant p.Arg329Gln in a POI case, which explains the phenotype. Functional analysis of the POF1B variant p.Arg329Gln showed diminished binding of the mutant protein to non-muscle actin, and the authors hypothesized a possible role for POF1B in pairing of meiotic chromosomes or as an anti-apoptotic factor.

ii) PMID: 34423420- novel homozygous missense variant p.K311T in a Chinese patient with POF, adjacent to the known p.R329Q variant, suggesting that would damage the capacity of POF1B to bind non-muscle actin filaments.

iii) PMID: 34707299 - homozygous missense variant p.(Arg329Gln) in a female with POI (identical to PMID:16773570).
Sources: Literature; to: Literature in OMIM- PMID:16773570- familial case with POF carrying homozygous missense variant R329Q, supported by functional evidence.

New papers:
i) PMID: 25676666- reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense variant p.Arg329Gln in a POI case, which explains the phenotype. Functional analysis of the POF1B variant p.Arg329Gln showed diminished binding of the mutant protein to non-muscle actin, and the authors hypothesized a possible role for POF1B in pairing of meiotic chromosomes or as an anti-apoptotic factor.

ii) PMID: 34423420- novel homozygous missense variant p.K311T in a Chinese patient with POF, adjacent to the known p.R329Q variant, suggesting that would damage the capacity of POF1B to bind non-muscle actin filaments.

iii) PMID: 34707299 - homozygous missense variant p.(Arg329Gln) in a female with POI (identical to PMID:16773570).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 POF1B Jasmine Chew changed review comment from: Literature in OMIM- PMID:16773570- familial case with POF carrying homozygous R329Q, supported by functional evidence.

New papers:
i) PMID: 25676666- reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense variant p.Arg329Gln in a POI case, which explains the phenotype. Functional analysis of the POF1B variant p.Arg329Gln showed diminished binding of the mutant protein to non-muscle actin, and the authors hypothesized a possible role for POF1B in pairing of meiotic chromosomes or as an anti-apoptotic factor.

ii) PMID: 34423420- novel homozygous missense variant p.K311T in a Chinese patient with POF, adjacent to the known p.R329Q variant, suggesting that would damage the capacity of POF1B to bind non-muscle actin filaments.

iii) PMID: 34707299 - homozygous missense variant p.(Arg329Gln) in a female with POI (identical to PMID:16773570).
Sources: Literature; to: Literature in OMIM- PMID:16773570- familial case with POF carrying homozygous R329Q, supported by functional evidence.

New papers:
i) PMID: 25676666- reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense variant p.Arg329Gln in a POI case, which explains the phenotype. Functional analysis of the POF1B variant p.Arg329Gln showed diminished binding of the mutant protein to non-muscle actin, and the authors hypothesized a possible role for POF1B in pairing of meiotic chromosomes or as an anti-apoptotic factor.

ii) PMID: 34423420- novel homozygous missense variant p.K311T in a Chinese patient with POF, adjacent to the known p.R329Q variant, suggesting that would damage the capacity of POF1B to bind non-muscle actin filaments.

iii) PMID: 34707299 - homozygous missense variant p.(Arg329Gln) in a female with POI (identical to PMID:16773570).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 POF1B Jasmine Chew gene: POF1B was added
gene: POF1B was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: POF1B was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: POF1B were set to 16773570; 34707299; 25676666; 34423420
Phenotypes for gene: POF1B were set to Premature ovarian failure 2B, MIM# 300604
Review for gene: POF1B was set to GREEN
Added comment: Literature in OMIM- PMID:16773570- familial case with POF carrying homozygous R329Q, supported by functional evidence.

New papers:
i) PMID: 25676666- reciprocal translocation between chromosomes X and 3 and an additional heterozygous missense variant p.Arg329Gln in a POI case, which explains the phenotype. Functional analysis of the POF1B variant p.Arg329Gln showed diminished binding of the mutant protein to non-muscle actin, and the authors hypothesized a possible role for POF1B in pairing of meiotic chromosomes or as an anti-apoptotic factor.

ii) PMID: 34423420- novel homozygous missense variant p.K311T in a Chinese patient with POF, adjacent to the known p.R329Q variant, suggesting that would damage the capacity of POF1B to bind non-muscle actin filaments.

iii) PMID: 34707299 - homozygous missense variant p.(Arg329Gln) in a female with POI (identical to PMID:16773570).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 PRDM9 Jasmine Chew gene: PRDM9 was added
gene: PRDM9 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PRDM9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM9 were set to 34257419
Phenotypes for gene: PRDM9 were set to Primary ovarian insufficiency, MONDO:0005387
Review for gene: PRDM9 was set to GREEN
Added comment: i) PMID: 34257419 (2021): 3 heterozygous variants in 4 unrelated premature ovarian insufficiency (POI) patients (P1,2- p.Arg77*, P3- p.Lys226Met, P4- p.Ile213Ser); All mutant proven to affect the H3K4 methyltransferase activity of the protein and more apoptotic oocytes were observed in Prdm9+/- mice ovaries indicating the heterozygous knockout oocytes were more susceptible to exogenous stress.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 PSMC3IP Jasmine Chew gene: PSMC3IP was added
gene: PSMC3IP was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PSMC3IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3IP were set to 21963259; 35352317; 34878148; 30406445; 29240891
Phenotypes for gene: PSMC3IP were set to Ovarian dysgenesis 3, MIM# 614324
Review for gene: PSMC3IP was set to GREEN
Added comment: Literature in OMIM- PMID:21963259

New papers (new variants reported)- PMID:35352317; 34878148; 30406445; 29240891 (Supported by functional evidence in 25820426)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 SOHLH1 Jasmine Chew gene: SOHLH1 was added
gene: SOHLH1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SOHLH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SOHLH1 were set to 25774885; 20506135; 28718531; 38448741; 34448846
Phenotypes for gene: SOHLH1 were set to Ovarian dysgenesis 5, MIM #617690; Spermatogenic failure 32, MIM #618115
Review for gene: SOHLH1 was set to GREEN
Added comment: Literature in OMIM- PMID:25774885; 20506135; 28718531

New papers for ovarian dysgenesis:
i) PMID: 38448741- novel homozygous missense variant (Ser92Leu) in three affected females from an inbred Mexican family with familial ovarian dysgenesis. Histological examination showed ovarian cortex marked by fibrosis and an almost complete absence of follicle, which was consistent with the findings in the gonads of Sohlh1-deficient mice (PMID: 16690745).

New papers for spermatogenic failure (new recessive-inheritance pattern of SOHLH1-associated male infertility):
i) PMID: 34448846- homozygous c.346-1G > A variant in a severe oligozoospermia (SOZ) patient, characterized with severely decreased sperm count. The homozygous variant leads to the sharp decrease in various germ cells and spermatogenesis dysfunction, which is similar to the phenotype of SOHLH1 knockout male mice (PMID: 30614095). Suggested that previously reported heterozygous c.346-1G > A variant is associated with teratozoospermia but not a direct cause for NOA and the homozygous c.346-1G > A variant impairs spermatogenesis and further leads to the reduced sperm count, eventually causing male infertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 BMP15 Jasmine Chew gene: BMP15 was added
gene: BMP15 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: BMP15 was set to Other
Publications for gene: BMP15 were set to 15136966; 16508750; 16464940; 19263482; 39850788; 35861920
Phenotypes for gene: BMP15 were set to Ovarian dysgenesis 2, MIM# 300510; Premature ovarian failure 4, MIM# 300510
Review for gene: BMP15 was set to GREEN
Added comment: Literature in OMIM (PMID: 15136966;16508750;16464940;19263482)- multiple affected females carrying monoallelic variants with POI+/- ovarian dysgenesis.

New papers reporting on biallelic variants in affected females:
i) PMID: 39850788- novel homozygous variant (p.C320Y) in 2 Palestinian sisters born to consanguineous parents with ovarian dysgenesis and primary amenorrhea; in-vitro assay also showed decreased in BMP signaling in cells expressing the homozygous BMP15 mutant when compared to the WT control.
ii) PMID: 35861920- novel compound heterozygous variant (p. R264Q and p. P359L) in two siblings with POI. Both missense variants reduced the level of the BMP15 protein and impaired the function of BMP15 in promoting granulosa cell proliferation in vitro.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 EIF4ENIF1 Jasmine Chew edited their review of gene: EIF4ENIF1: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.17 EIF4ENIF1 Jasmine Chew gene: EIF4ENIF1 was added
gene: EIF4ENIF1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EIF4ENIF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF4ENIF1 were set to 23902945; 39827467; 36030004; 38604507; 31810472; 33095795
Phenotypes for gene: EIF4ENIF1 were set to Primary ovarian insufficiency, MONDO:0005387, EIF4ENIF1-related
Added comment: i) PMID: 23902945- heterozygous stop gained p. Ser429X variant in 6 POI-affected women segregated in a large family; mRNA in white blood cells from 3 affected women demonstrated nonsense mutant transcript at a decreased proportion compared with that in gDNA, suggesting haploinsufficiency or dominant negative effect. A stop-gain mouse model was created for the heterozygous variant by PMID: 39827467 (2025), which replicated POI phenotype in women (i.e., decreased reproductive lifespan and early oocyte loss).

ii) PMID: 36030004 - two variants, p.R4del and (p.G954A in two sporadic Han Chinese POI patients. Western blot analysis further demonstrated that both of the two variants exhibited reduced mRNA and protein expression levels compared with the wild-type in vitro

iii) PMID: 38604507 - novel missense variant (p.R208H) in a patient with POI and in vitro transfection study showed that overexpression R208H significantly (P < 0.0001) lowered the overall translation efficiency, whereas exhibiting a reduced translation inhibitory effect on high-TE genes (TE > 2 in GFP control group).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 SYCP3 Jasmine Chew edited their review of gene: SYCP3: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.17 KHDC3L Jasmine Chew edited their review of gene: KHDC3L: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.17 ZP1 Jasmine Chew gene: ZP1 was added
gene: ZP1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ZP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZP1 were set to 24670168; 30810869; 36385415; 39380244; 36529558
Phenotypes for gene: ZP1 were set to Oocyte/zygote/embryo maturation arrest 1, MIM# 615774
Review for gene: ZP1 was set to GREEN
Added comment: Literature in OMIM (PMID: 24670168;30810869)- familial cases with homozygous missense/frameshift variant in affected women with primary infertility due to oocyte maturation defect; supported by functional evidence.

New papers:
i) PMID: 36385415- homozygous nonsense variant p.Gln210Ter in a case with primary infertility (C19)

ii) PMID: 39380244;36529558- homozygous missense variants in the same AA position (p.Arg366Trp and p.Arg366Gln) in unrelated females with with empty follicle syndrome; supported by functional evidence
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 ZP2 Jasmine Chew gene: ZP2 was added
gene: ZP2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ZP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZP2 were set to 29895852; 30810869; 39443359; 33604805
Phenotypes for gene: ZP2 were set to Oocyte/zygote/embryo maturation arrest 6, MIM# 618353
Added comment: Literature in OMIM (PMID: 29895852; 30810869)- familial cases with homozygous variants (splice and missense) reported in affected women with defective/absent oocyte zona pellucida, supported by functional evidence

New papers-
i) PMID: 39443359- novel compound heterozygous variant (c.1924C > T and c.1695-2A > G) in a Chinese Han family with primary female infertility due to oocyte degeneration caused by absent/thin ZP; both variants (c.1924C > T and c.1695-2A > G) resulted in truncated ZP2 proteins (p.R642X and p.C566Hfs*2) that lost the transmembrane domain, which prevented the secretion of the mutant ZP2 proteins and produced a structurally abnormal ZP.

ii) PMID: 33604805- novel homozygous frameshift variant (p.Q412Rfs*17) in two infertile sisters in a family with a thin zona pellucida (ZP) phenotype, supported by functional evidence.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 TACC3 Jasmine Chew edited their review of gene: TACC3: Changed phenotypes: Female infertility due to oocyte meiotic arrest, MONDO:0044626
Infertility and Recurrent Pregnancy Loss v0.17 TACC3 Jasmine Chew changed review comment from: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.

Note: couldn't access MONDO # as website down (phenotypes to be updated); to: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Infertility and Recurrent Pregnancy Loss v0.17 ZP3 Jasmine Chew gene: ZP3 was added
gene: ZP3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ZP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ZP3 were set to 28886344; 30810869; 39932488; 37908588
Phenotypes for gene: ZP3 were set to Oocyte/zygote/embryo maturation arrest 3, MIM# 617712
Review for gene: ZP3 was set to GREEN
Added comment: Literature in OMIM (PMID: 28886344;30810869)- familial cases with heterozygous missense variants supported by functional evidence (dominant-negative effect).

New papers-
i) PMID: 39932488- 4 heterozygous missense variants (2 novel, 2 known) with primary infertility, characterized by zona pellucida abnormalities or abnormal oocyte morphology. Also quoted that "To date, no studies have reported successful pregnancies in patients with ZP3 variants, suggesting that ZP3 plays an indispensable role in zona pellucida assembly and that ZP3 deficiency currently has no effective solution."

ii) PMID: 37908588- novel homozygous missense variant in a female with empty follicle syndrome (EFS), who failed to retrieve any oocytes after three rounds of ovarian stimulation despite the presence of large follicles.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 TUBB8 Jasmine Chew gene: TUBB8 was added
gene: TUBB8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TUBB8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TUBB8 were set to 26789871; 27273344; 33970371; 39834092
Phenotypes for gene: TUBB8 were set to Oocyte/zygote/embryo maturation arrest 2, MIM# 616780
Review for gene: TUBB8 was set to GREEN
Added comment: Literature from OMIM (PMID: 26789871;27273344)- multiple familial cases and supporting functional evidence (monoallelic- dominant-negative effect; biallelic- functionally null, disrupt spindle assembly and cause abnormalities in oocyte maturation, fertilization, and embryonic development)

More recent supporting evidence-
i) PMID: 39834092- functional evidence elucidating how TUBB8 missense variants cause oocyte maturation arrest
ii) PMID: 33970371- 29 variants in TUBB8 from 32 independent families with female infertility, of which 20 were novel, expanding the variant spectrum of TUBB8 (i.e., extremely involved in complete cleavage failure and embryonic arrest)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 AURKC Jasmine Chew gene: AURKC was added
gene: AURKC was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: AURKC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AURKC were set to 17435757; 19147683; 21733974
Phenotypes for gene: AURKC were set to Spermatogenic failure 5, MIM #243060
Review for gene: AURKC was set to GREEN
Added comment: i) PMID: 17435757- homozygous 1bp del (c.144delC; 603495.0001) in 10 infertile men (4 were unrelated French citizens of African descent) with a large-headed sperm phenotype, which resulted in premature termination of translation, yielding a truncated protein that lacks the kinase domain
ii) PMID: 19147683 - homozygous c.144delC found in 31 patients and compound heterozygous for c.144delC and a missense variant (C229Y) in 30 patients with large-headed spermatozoa

iii) PMID: 21733974- compound heterozygous for the c.144delC variant and a splice variant ((c.436-2A-G; predicted to cause skipping of exon 5) in 2 infertile brothers of Tunisian descent with macrozoospermia and a younger sister who had yet tried to achieve pregnancy
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.17 CDC20 Zornitza Stark Marked gene: CDC20 as ready
Infertility and Recurrent Pregnancy Loss v0.17 CDC20 Zornitza Stark Gene: cdc20 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.17 CDC20 Zornitza Stark Classified gene: CDC20 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.17 CDC20 Zornitza Stark Gene: cdc20 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.16 CCNB3 Zornitza Stark Marked gene: CCNB3 as ready
Infertility and Recurrent Pregnancy Loss v0.16 CCNB3 Zornitza Stark Gene: ccnb3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.16 CCNB3 Zornitza Stark Phenotypes for gene: CCNB3 were changed from to Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CCNB3-related
Infertility and Recurrent Pregnancy Loss v0.15 CCNB3 Zornitza Stark reviewed gene: CCNB3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Recurrent pregnancy loss, susceptibility to, MONDO:0000144, CCNB3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.15 CCNB3 Zornitza Stark Classified gene: CCNB3 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.15 CCNB3 Zornitza Stark Gene: ccnb3 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.14 DMRT1 Zornitza Stark Marked gene: DMRT1 as ready
Infertility and Recurrent Pregnancy Loss v0.14 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.14 DMRT1 Zornitza Stark Phenotypes for gene: DMRT1 were changed from to Azoospermia, MONDO:0100459, DMRT1-related
Infertility and Recurrent Pregnancy Loss v0.13 DMRT1 Zornitza Stark Classified gene: DMRT1 as Amber List (moderate evidence)
Infertility and Recurrent Pregnancy Loss v0.13 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Amber List (Moderate Evidence).
Infertility and Recurrent Pregnancy Loss v0.12 DMRT1 Zornitza Stark commented on gene: DMRT1: Rare variants enriched in azoospermia cohorts. However, variants are missense, pathogenicity more difficult to determine in the absence of segregation or other data.
Infertility and Recurrent Pregnancy Loss v0.12 DMRT1 Zornitza Stark reviewed gene: DMRT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Azoospermia, MONDO:0100459, DMRT1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.12 DMRT1 Jasmine Chew gene: DMRT1 was added
gene: DMRT1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DMRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DMRT1 were set to 26139570; 38511217; 39777458
Review for gene: DMRT1 was set to GREEN
Added comment: Literature in OMIM- PMID: 26139570

New papers:
i) PMID: 38511217- heterozygous missense variant (K68N) in a Japanese man (case 13) with non-obstructive azoospermia (NOA)

ii)PMID: 39777458- heterozygous missense variant (p.Pro74Leu) in two infertile Croatian brothers with NOA in the highly conserved position within the DNA binding DM domain of the protein, and EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Also identified additional nine infertile men with idiopathic NOA or severe oligozoospermia as carriers of missense variants (see Table 2) located in critical functional domains of DMRT1.

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 DPY19L2 Jasmine Chew gene: DPY19L2 was added
gene: DPY19L2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DPY19L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPY19L2 were set to 15533374; 21397064; 21397064; 26516168; 30333325; 39045326
Phenotypes for gene: DPY19L2 were set to Spermatogenic failure 9, MIM# 613958
Review for gene: DPY19L2 was set to GREEN
Added comment: Literature from OMIM- PMID:15533374, 21397064, 21397064

New papers:
i) PMID: 26516168- In a cohort of Tunisian globozoospermic patients, 11 had homozygous DPY19L2 deletion, 2 had homozygous missense variant p.R298, and a patient with a novel homozygous splice site variant.

ii) PMID: 30333325- In a cohort of Chinese globozoospermic patients, 5 had DPY19L2 deletions and the other four patients carried novel DPY19L2 point variants.

iii) PMID: 39045326- homozygous variants (Arg 574Ter and Pro241Leu) in two patients with globozoospermia
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 FKBP6 Jasmine Chew gene: FKBP6 was added
gene: FKBP6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: FKBP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP6 were set to 36150389
Phenotypes for gene: FKBP6 were set to Spermatogenic failure 77, MIM# 620103
Review for gene: FKBP6 was set to GREEN
Added comment: i) PMID: 36150389- compound heterozygous/ homozygous LOF variants in 6 unrelated infertile men (Dutch/German/Brazilian/Kyrgyz) with spermatogenic failure. Analysis of testicular histology was consistent with onset of germ cell loss in late meiosis and early spermiogenesis. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 GGN Jasmine Chew changed review comment from: i) PubMed: 31985809 (2020)- homozygous 1bp deletion causing a frameshift predicted to result in a premature termination codon (Gly424AlafsTer65) in 2 Turkish brothers with infertility due to globozoospermia.

ii) PubMed: 33108537 (2021)- homozygous 22bp deletion in an infertile man with globozoospermia causing a frameshift predicted to result in a premature termination codon (Leu139ArgfsTer8). The 146-amino acid mutant protein would lack the GGNBP2 (612275) and OAZ3 (605138) interaction domain, and the GGNBP1 (609495) interaction domain would be partially truncated.

iii) PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.
Sources: Literature; to: i) PubMed: 31985809 (2020)- homozygous 1bp deletion causing a frameshift predicted to result in a premature termination codon (Gly424AlafsTer65) in 2 Turkish brothers with infertility due to globozoospermia.

ii) PubMed: 33108537 (2021)- homozygous 22bp deletion in an infertile man with globozoospermia causing a frameshift predicted to result in a premature termination codon (Leu139ArgfsTer8). The 146-amino acid mutant protein would lack the GGNBP2 (612275) and OAZ3 (605138) interaction domain, and the GGNBP1 (609495) interaction domain would be partially truncated.

iii) PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 GGN Jasmine Chew changed review comment from: i) PubMed: 31985809 (2020)- hom 1bp del causing a frameshift predicted to result in a premature termination codon (Gly424AlafsTer65) in 2 Turkish brothers with infertility due to globozoospermia.

ii) PubMed: 33108537 (2021)- hom 22bp del in an infertile man with globozoospermia causing a frameshift predicted to result in a premature termination codon (Leu139ArgfsTer8). The 146-amino acid mutant protein would lack the GGNBP2 (612275) and OAZ3 (605138) interaction domain, and the GGNBP1 (609495) interaction domain would be partially truncated.

iii) PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.
Sources: Literature; to: i) PubMed: 31985809 (2020)- homozygous 1bp deletion causing a frameshift predicted to result in a premature termination codon (Gly424AlafsTer65) in 2 Turkish brothers with infertility due to globozoospermia.

ii) PubMed: 33108537 (2021)- homozygous 22bp deletion in an infertile man with globozoospermia causing a frameshift predicted to result in a premature termination codon (Leu139ArgfsTer8). The 146-amino acid mutant protein would lack the GGNBP2 (612275) and OAZ3 (605138) interaction domain, and the GGNBP1 (609495) interaction domain would be partially truncated.

iii) PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 GGN Jasmine Chew gene: GGN was added
gene: GGN was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: GGN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GGN were set to Spermatogenic failure 69, MIM# 619826
Mode of pathogenicity for gene: GGN was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GGN was set to GREEN
Added comment: i) PubMed: 31985809 (2020)- hom 1bp del causing a frameshift predicted to result in a premature termination codon (Gly424AlafsTer65) in 2 Turkish brothers with infertility due to globozoospermia.

ii) PubMed: 33108537 (2021)- hom 22bp del in an infertile man with globozoospermia causing a frameshift predicted to result in a premature termination codon (Leu139ArgfsTer8). The 146-amino acid mutant protein would lack the GGNBP2 (612275) and OAZ3 (605138) interaction domain, and the GGNBP1 (609495) interaction domain would be partially truncated.

iii) PMID: 23451117 (2013)- Ggn null mouse line demonstrated that s complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 NLRP5 Jasmine Chew gene: NLRP5 was added
gene: NLRP5 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: NLRP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NLRP5 were set to 30877238; 32222962; 35091966; 35946397; 33583041
Phenotypes for gene: NLRP5 were set to Oocyte/zygote/embryo maturation arrest 19, MIM# 620333
Review for gene: NLRP5 was set to GREEN
Added comment: Literature in OMIM- PMID: 30877238, 32222962, 35091966, 35946397

New evidence:
i) PMID: 33583041- homozygous missense variant (p.Asp365Asn) in an Iranian woman with 2 years of infertility, IUI-twin (HM + fetus), and two complete hydatidiform mole
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 PDHA2 Jasmine Chew changed review comment from: i) PMID: 29581481- a homozygous missense variant (M227V) in 3 infertile brothers from a consanguineous Algerian family with male infertility (owing to azoospermia, sperm immotility or necrospermia)

ii) PubMed: 35172124- previously reported homozygous missense variant (M227V) in 2 unrelated infertile Tunisian men with NOA
Sources: Literature; to: i) PMID: 29581481- a homozygous missense variant (M227V) in 3 infertile brothers from a consanguineous Algerian family with male infertility (owing to azoospermia, sperm immotility or necrospermia)

ii) PMID: 35172124- previously reported homozygous missense variant (M227V) in 2 unrelated infertile Tunisian men with NOA
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 PDHA2 Jasmine Chew gene: PDHA2 was added
gene: PDHA2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PDHA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDHA2 were set to 29581481; 35172124
Phenotypes for gene: PDHA2 were set to Spermatogenic failure 70, MIM# 619828
Review for gene: PDHA2 was set to GREEN
Added comment: i) PMID: 29581481- a homozygous missense variant (M227V) in 3 infertile brothers from a consanguineous Algerian family with male infertility (owing to azoospermia, sperm immotility or necrospermia)

ii) PubMed: 35172124- previously reported homozygous missense variant (M227V) in 2 unrelated infertile Tunisian men with NOA
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 SYCP3 Jasmine Chew reviewed gene: SYCP3: Rating: ; Mode of pathogenicity: None; Publications: 14643120, 19110213; Phenotypes: Spermatogenic failure 4, MIM# 270960, Recurrent pregnancy loss 4, MIM# 270960; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.12 SYCP3 Jasmine Chew Deleted their review
Infertility and Recurrent Pregnancy Loss v0.12 SYCP3 Jasmine Chew reviewed gene: SYCP3: Rating: ; Mode of pathogenicity: None; Publications: 14643120, 19110213; Phenotypes: Spermatogenic failure 4, MIM# 270960, Recurrent pregnancy loss 4, MIM# 270960; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Infertility and Recurrent Pregnancy Loss v0.12 RXFP2 Jasmine Chew changed review comment from: i) PMID: 39222519 (2024)- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.

ii) PMID: 37208861 (2023)- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies).

iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay.

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature; to: i) PMID: 39222519- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.

ii) PMID: 37208861- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies).

iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay.

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 RXFP2 Jasmine Chew gene: RXFP2 was added
gene: RXFP2 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: RXFP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RXFP2 were set to 39222519; 37208861; 38430325
Review for gene: RXFP2 was set to GREEN
Added comment: i) PMID: 39222519 (2024)- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism.

ii) PMID: 37208861 (2023)- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies).

iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay.

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 SLC26A8 Jasmine Chew changed review comment from: i) PMID: 23582645- 3 heterozygous missense variants in 3 unrelated infertile men, and studies in transfected CHO-K1 cells revealed reduced interactions with CFTR and complete failure of the all three mutant to activate CFTR-dependent anion transport. Immunoblot analysis also showed that the mutant protein was significantly less abundant than wildtype and the decreased abundance of the mutant protein results from instability and proteasomal degradation.

ii) PMID: 34923715- Compound heterozygous variants in two unrelated infertile Chinese men with severe asthenozoospermia. The sperm motility of these homozygous probands was severely reduced, compared to the moderately reduced motility of sperm from the previously reported heterozygous probands (confirmed by immunoblot), consistent with SLC26A8 being the cause of their infertility phenotype,

iii) PMID: 35181959- 3 heterozygous variants ( 2-bp deletion, V731I, 1-bp deletion) in 3 unrelated infertile men with asthenoteratozoospermia, and although transfection study showed a significantly reduction of SLC26A8 expression to nearly absence in transfected HEK293 cells, immunostaining of patient sperm showed no difference in SLC26A8 expression compared to control sperm and western blot analysis of spermatozoa lysates confirmed the similar expression of SLC26A8 between patient and control sperm. Also mentioned that previous studies (PMID: 22121115 and PMID: 17517695) had shown that Slc26a8 +/- mice were fertile, whereas Slc26a8-null mice were infertile, the authors suggested that heterozygous SLC26A8 variants might not be the direct cause of the asthenoteratozoospermic phenotype observed in infertile men, and that SLC26A8-associated male infertility is likely an autosomal recessive disorder.
Sources: Literature; to: i) PMID: 23582645- 3 heterozygous missense variants in 3 unrelated infertile men, and studies in transfected CHO-K1 cells revealed reduced interactions with CFTR and complete failure of the all three mutant to activate CFTR-dependent anion transport.

ii) PMID: 34923715- Compound heterozygous variants in two unrelated infertile Chinese men with severe asthenozoospermia. The sperm motility of these homozygous probands was severely reduced, compared to the moderately reduced motility of sperm from the previously reported heterozygous probands (confirmed by immunoblot), consistent with SLC26A8 being the cause of their infertility phenotype,

iii) PMID: 35181959- 3 heterozygous variants ( 2-bp deletion, V731I, 1-bp deletion) in 3 unrelated infertile men with asthenoteratozoospermia. Although transfection study showed a significantly reduction of SLC26A8 expression to nearly absence in transfected HEK293 cells, immunostaining of patient sperm showed no difference in SLC26A8 expression compared to control sperm and western blot analysis of spermatozoa lysates confirmed the similar expression of SLC26A8 between patient and control sperm. Also mentioned that previous studies (PMID: 22121115 and PMID: 17517695) had shown that Slc26a8 +/- mice were fertile, whereas Slc26a8-null mice were infertile, the authors suggested that heterozygous SLC26A8 variants might not be the direct cause of the asthenoteratozoospermic phenotype observed in infertile men, and that SLC26A8-associated male infertility is likely an autosomal recessive disorder.
Infertility and Recurrent Pregnancy Loss v0.12 SLC26A8 Jasmine Chew gene: SLC26A8 was added
gene: SLC26A8 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SLC26A8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC26A8 were set to 23582645; 34923715; 35181959
Phenotypes for gene: SLC26A8 were set to Spermatogenic failure 3, MIM# 606766
Review for gene: SLC26A8 was set to GREEN
Added comment: i) PMID: 23582645- 3 heterozygous missense variants in 3 unrelated infertile men, and studies in transfected CHO-K1 cells revealed reduced interactions with CFTR and complete failure of the all three mutant to activate CFTR-dependent anion transport. Immunoblot analysis also showed that the mutant protein was significantly less abundant than wildtype and the decreased abundance of the mutant protein results from instability and proteasomal degradation.

ii) PMID: 34923715- Compound heterozygous variants in two unrelated infertile Chinese men with severe asthenozoospermia. The sperm motility of these homozygous probands was severely reduced, compared to the moderately reduced motility of sperm from the previously reported heterozygous probands (confirmed by immunoblot), consistent with SLC26A8 being the cause of their infertility phenotype,

iii) PMID: 35181959- 3 heterozygous variants ( 2-bp deletion, V731I, 1-bp deletion) in 3 unrelated infertile men with asthenoteratozoospermia, and although transfection study showed a significantly reduction of SLC26A8 expression to nearly absence in transfected HEK293 cells, immunostaining of patient sperm showed no difference in SLC26A8 expression compared to control sperm and western blot analysis of spermatozoa lysates confirmed the similar expression of SLC26A8 between patient and control sperm. Also mentioned that previous studies (PMID: 22121115 and PMID: 17517695) had shown that Slc26a8 +/- mice were fertile, whereas Slc26a8-null mice were infertile, the authors suggested that heterozygous SLC26A8 variants might not be the direct cause of the asthenoteratozoospermic phenotype observed in infertile men, and that SLC26A8-associated male infertility is likely an autosomal recessive disorder.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 SYCP3 Jasmine Chew Deleted their review
Infertility and Recurrent Pregnancy Loss v0.12 SYCP3 Jasmine Chew gene: SYCP3 was added
gene: SYCP3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SYCP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYCP3 were set to 14643120; 19110213
Phenotypes for gene: SYCP3 were set to Spermatogenic failure 4, Recurrent pregnancy loss 4, MIM# 270960
Review for gene: SYCP3 was set to GREEN
Added comment: Spermatogenic failure 4, MIM# 270960
i) PMID: 14643120- identified a heterozygous 1-bp deletion (643delA) in 2 unrelated patients with azoospermia with with maturation arrest , resulting in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the protein. The mutant protein showed greatly reduced interaction with the wildtype protein in vitro and interfered with SYCP3 fiber formation in cultured cells. The results suggested that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein by dominant-negative interference.

Pregnancy loss, recurrent, 4, MIM# 270960
i) PMID: 19110213- identified a heterozygous deletion and a point variant (-16delACTT in intron 7 and 657T-C transition at the last nucleotide of exon 8) in 2 of the women with recurrent pregnancy loss that were not found in 150 fertile women. Both mutant proteins were shown to inhibit normal fiber formation of SYCP3 when coexpressed in a heterologous system. This suggested that the heterozygous variants are likely to form aberrant lateral elements in the synaptonemal complex in a dominant-negative manner, possibly leading to abnormal chromosomal behavior in meiosis I during oogenesis that might lead to recurrent miscarriage. Also noted that the SYCP3-related phenotype in humans, in which affected males are infertile whereas affected females have recurrent pregnancy loss, is similar to that seen in Sycp3-deficient mice (Yuan et al., 2000; Yuan et al., 2002).
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 KHDC3L Jasmine Chew gene: KHDC3L was added
gene: KHDC3L was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: KHDC3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KHDC3L were set to 21885028; 19246479; 23232697; 31847873; 31609975; 29606347
Phenotypes for gene: KHDC3L were set to Recurrent hydatidiform mole 2, MIM# 614293
Added comment: Biallelic variants have been reported for several unrelated families with recurrent complete hydatidiform mole (CHM) pregnancy- predominantly biparental and RPL- PMID: 21885028, 19246479, 23232697.

New evidence-
i) PMID 31847873: homozygous LOF variant in a woman with multiple consanguineous marriages in her extended family and history of 2 biparental complete hydatidiform mole (BiCHM) and methylation study on her oocytes revealed a genome-wide deficit of DNA methylation compared with normal human oocytes.

ii) PMID: 31609975- two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and homologous recombination (HR) repair. Also provided functional evidence that KHDC3L dysfunction causes PARP1 inhibition and HR-mediated DNA repair deficiency, which is synthetically lethal.

iii) PMID: 29606347- a novel homozygous frameshift p.Q15Rfs*25 variant in a female patient (II-1) from family 4 with a history of 2 spontaneous abortions and x2 partial hydatidiform moles, and her embryos formed after ICSI are fertilized normally but arrest at the morula stage.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 PADI6 Jasmine Chew gene: PADI6 was added
gene: PADI6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PADI6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PADI6 were set to 29693651; 33583041; 33221824; 27730629; 27545678
Phenotypes for gene: PADI6 were set to Oocyte/zygote/embryo maturation arrest 16, #MIM 617234
Review for gene: PADI6 was set to GREEN
Added comment: i) PMID: 29693651- a compound het variant (N598S and R682Q) in a female with a total of six pregnancy losses from natural spontaneous conceptions, two of them were initially diagnosed as miscarriages and four as molar pregnancy.

ii) PMID: 33583041- a novel homozygous missense variant (p.Ile599Asn) in a woman with a total of seven pregnancy losses from spontaneous conceptions, four HMs including two with fetuses and three miscarriages.

iii) PMID: 33221824- a compound het variant (p.Thr372Ala and p.Trp690*) in a German woman with and miscarriages and also occurrence of multilocus imprinting disturbance (MLID) in two children each carrying a heterozygous variant..

iv) PMID: 27730629- a homozygous nonsense variant (p.Arg457*) in a Saudi woman with primary infertility and early development arrest during embryonic cleavage stages after in vitro fertilization.

v) PMID: 27545678- homozygous nonsense variant (p.Gln381∗) in one familial case (consisting of three sisters) and compound heterozygous variants in 2 other unrelated patients with primary infertility and early development arrest during embryonic cleavage stages after in vitro fertilization.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 CCNB3 Jasmine Chew changed review comment from: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29)
ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II.
iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I.

Supporting mouse evidence:
iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos.
v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development).

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Sources: Literature; to: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29)
ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II.
iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I.

Supporting mouse evidence:
iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos.
v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development).

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 CCNB3 Jasmine Chew edited their review of gene: CCNB3: Changed rating: GREEN
Infertility and Recurrent Pregnancy Loss v0.12 CCNB3 Jasmine Chew gene: CCNB3 was added
gene: CCNB3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CCNB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCNB3 were set to 35722368; 32938693; 34021051; 30770433; 34850816
Added comment: i) PMID: 35722368- homozygous missense variant (p.P119Q) in the female of unexplained recurrent pregnancy loss (RPL) couple (couple 29)
ii) PMID: 32938693- homozygous missense variant (p.V1251D) in two sisters with RPL and two of their POCs were characterised and found to be triploid digynic due to the failure of meiosis II.
iii) PMID: 34021051- novel homozygous frameshift variant (p.Val1321Glyfs*4, due to splicing causing exon skipping) in a patient with 16 RPL and one of her miscarriages is triploid digynic resulted from the failure of meiosis I.

Supporting mouse evidence:
iv) PMID: 30770433- Ccnb3 knockout also causes female infertility due to the failure of metaphase to anaphase transition in meiosis I and the extrusion of the first polar body. The infertility in these mice appeared to be due to embryonic lethality before embryonic day 7.5 and some of their oocytes fertilised by intracytoplasmic sperm injection led to triploid embryos.
v) PMID: 34850816- Ccnb3-deficient mouse model is similar to a human infertility condition—recurrent pregnancy loss (RPL). Their findings demonstrate that the triploidy of embryos derived from Ccnb3-deficient oocytes is the primary cause of embryo death (i.e., such embryos can be rescued with euploid nuclei, whereas cytoplasmic Ccnb3 transcript is dispensable for zygotic genome activation and embryo development).

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 CDC20 Jasmine Chew gene: CDC20 was added
gene: CDC20 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: CDC20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC20 were set to 32666501; 33683667; 33898437; 34218387
Phenotypes for gene: CDC20 were set to Oocyte/zygote/embryo maturation arrest 14, MIM# 620276
Review for gene: CDC20 was set to GREEN
Added comment: i) PMID: 32666501- Biallelic (homozygous/compound heterozygous) variants in 5 unrelated Chinese women with infertility due to oocyte maturation arrest. Knocked down mouse oocytes showed an metaphase I (MI) arrest phenotype that could be rescued by injection of wildtype human CDC20 cRNA; all of the variants significantly reduced the ability of CDC20 to rescue the phenotype.

ii) PMID: 33683667- a compound heterozygous (missense and nonsense) variant in a Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest.

iii) PMID: 33898437- 4 patients from 3 Chinese families with homozygous or compound heterozygous variants with infertility due to oocyte maturation arrest, fertilization failure, and early embryonic arrest. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that the homozygous and compound heterozygous variants significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest).

iv) PMID: 34218387- homozygous missense variant in a Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of MII oocytes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 TACC3 Jasmine Chew changed review comment from: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Sources: Literature; to: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.

Note: couldn't access MONDO # as website down (phenotypes to be updated)
Infertility and Recurrent Pregnancy Loss v0.12 TACC3 Jasmine Chew gene: TACC3 was added
gene: TACC3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TACC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TACC3 were set to 36395215
Review for gene: TACC3 was set to GREEN
Added comment: PMID: 36395215- compound heterozygous variants (Patient 1- p.Ser177Thr/p.Pro395Arg, Patient 2- p.Lys225_Cys236del/p.Gly631Val) in two unrelated females presented with oocyte maturation arrest and undetectable spindles on both polarization and fluorescence microscopy. Their oocytes lacked huoMTOCs and had poorly organized microtubules, similar to the phenotype of TACC3 depletion in vitro, which suggests a loss-of-function mechanism causing oocyte maturation arrest and infertility.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 ELL3 Jasmine Chew gene: ELL3 was added
gene: ELL3 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: ELL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELL3 were set to 39820605
Review for gene: ELL3 was set to GREEN
Added comment: PMID:39820605- 8 different heterozygous variants (5 missense, 3 splicing) in 8 unrelated couples who experienced consecutive early miscarriages due to embryonic aneuploidy. For the three splice variants, mini-gene splicing assays revealed that all led to abnormal splicing, and consequently premature termination of translation or exon skipping, consistent with LOF effect. Findings from functional analysis on human oocytes and knockout mouse oocytes overall supporting that ELL3 depletion increases the incidence of meiotic spindle abnormality and oocyte aneuploidy.
Note: couldn't access MONDO # as website down (phenotypes to be updated)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 WNT6 Jasmine Chew gene: WNT6 was added
gene: WNT6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: WNT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT6 were set to 36385415; 25750203
Phenotypes for gene: WNT6 were set to recurrent pregnancy loss susceptibility, MONDO:0000144
Review for gene: WNT6 was set to GREEN
Added comment: i) PMID: 36385415- heterozygous missense variant (p.Arg70Gly) in a female with recurrent pregnancy loss (C21)

ii) PMID: 25750203- four novel heterozygous (checked Sanger traces) variants (i.e, one missense P.Leu148Arg, one synonymous c. 522C>T, one variant in intron 1 c. 297+40G>A, and one variant in the 3′UTR c. 1127G>A ) in 4 women with unexplained recurrent miscarriages (RM), but only the missense variant was shown to affect the functional region of WNT6 that might explain the unexplained RM
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 USP26 Jasmine Chew gene: USP26 was added
gene: USP26 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: USP26 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: USP26 were set to 34202084; 27089915
Phenotypes for gene: USP26 were set to Spermatogenic failure, X-linked 6, MIM# 301101
Review for gene: USP26 was set to GREEN
Added comment: i) PMID: 34202084- hemizygous missense variants in 2 unrelated affected Chinese men with infertility due to asthenoteratozoospermia (R825G in proband H002, and N799S in proband H042) and functional analysis showed markedly reduced USP26 mRNA and protein levels in patient sperm.

ii) PMID: 27089915- a novel hemizygous missense variant R344W in two affected Chinese men with non-obstructive azoospermia, which has been shown functionally to have reduce binding affinity and deubiquitinating activity of USP26 to androgen receptors.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.12 TEX11 Zornitza Stark Marked gene: TEX11 as ready
Infertility and Recurrent Pregnancy Loss v0.12 TEX11 Zornitza Stark Gene: tex11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.12 TEX11 Zornitza Stark Phenotypes for gene: TEX11 were changed from #MIM:309120 to Spermatogenic failure, X-linked 2, MIM# 309120
Infertility and Recurrent Pregnancy Loss v0.11 TEX11 Zornitza Stark Classified gene: TEX11 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.11 TEX11 Zornitza Stark Gene: tex11 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.10 TEX11 Zornitza Stark reviewed gene: TEX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure, X-linked 2, MIM# 309120; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Infertility and Recurrent Pregnancy Loss v0.10 SPAG6 Zornitza Stark Marked gene: SPAG6 as ready
Infertility and Recurrent Pregnancy Loss v0.10 SPAG6 Zornitza Stark Gene: spag6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.10 SPAG6 Zornitza Stark Phenotypes for gene: SPAG6 were changed from MONDO:0004983 to Spermatogenic failure, MONDO:0004983, SPAG6-related
Infertility and Recurrent Pregnancy Loss v0.9 SPAG6 Zornitza Stark Classified gene: SPAG6 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.9 SPAG6 Zornitza Stark Gene: spag6 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.8 SPAG6 Zornitza Stark reviewed gene: SPAG6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure, MONDO:0004983, SPAG6-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.8 SEPT12 Zornitza Stark Marked gene: SEPT12 as ready
Infertility and Recurrent Pregnancy Loss v0.8 SEPT12 Zornitza Stark Gene: sept12 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.8 SEPT12 Zornitza Stark Phenotypes for gene: SEPT12 were changed from #MIM:614822 to Spermatogenic failure 10, MIM#614822
Infertility and Recurrent Pregnancy Loss v0.7 SEPT12 Zornitza Stark Classified gene: SEPT12 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.7 SEPT12 Zornitza Stark Gene: sept12 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.6 SEPT12 Zornitza Stark reviewed gene: SEPT12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 10, MIM#614822; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.6 PLCZ1 Zornitza Stark Marked gene: PLCZ1 as ready
Infertility and Recurrent Pregnancy Loss v0.6 PLCZ1 Zornitza Stark Gene: plcz1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.6 PLCZ1 Zornitza Stark Phenotypes for gene: PLCZ1 were changed from #MIM:617214 to Spermatogenic failure 17, MIM# 617214
Infertility and Recurrent Pregnancy Loss v0.5 PLCZ1 Zornitza Stark Classified gene: PLCZ1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.5 PLCZ1 Zornitza Stark Gene: plcz1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.4 PLCZ1 Zornitza Stark reviewed gene: PLCZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 17, MIM# 617214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Infertility and Recurrent Pregnancy Loss v0.4 EXO1 Zornitza Stark Marked gene: EXO1 as ready
Infertility and Recurrent Pregnancy Loss v0.4 EXO1 Zornitza Stark Gene: exo1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.4 EXO1 Zornitza Stark Phenotypes for gene: EXO1 were changed from MONDO:0005387 to Primary ovarian failure, MONDO:0005387, EXO1-related
Infertility and Recurrent Pregnancy Loss v0.3 EXO1 Zornitza Stark Classified gene: EXO1 as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.3 EXO1 Zornitza Stark Gene: exo1 has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.2 EXO1 Zornitza Stark reviewed gene: EXO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ovarian failure, MONDO:0005387, EXO1-related; Mode of inheritance: None
Infertility and Recurrent Pregnancy Loss v0.2 DDX3Y Zornitza Stark Marked gene: DDX3Y as ready
Infertility and Recurrent Pregnancy Loss v0.2 DDX3Y Zornitza Stark Gene: ddx3y has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.2 DDX3Y Zornitza Stark Phenotypes for gene: DDX3Y were changed from MONDO:0100459 to Azoospermia, MONDO:0100459, DDX3Y-related
Infertility and Recurrent Pregnancy Loss v0.1 DDX3Y Zornitza Stark Classified gene: DDX3Y as Green List (high evidence)
Infertility and Recurrent Pregnancy Loss v0.1 DDX3Y Zornitza Stark Gene: ddx3y has been classified as Green List (High Evidence).
Infertility and Recurrent Pregnancy Loss v0.0 TEX11 Jasmine Chew gene: TEX11 was added
gene: TEX11 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: TEX11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TEX11 were set to 25970010; 29661171; 34621296; 37124723
Phenotypes for gene: TEX11 were set to #MIM:309120
Review for gene: TEX11 was set to GREEN
Added comment: i) PMID:25970010- hemizygous variants in 7 out of of 289 azoospermic men, including a 90kb exonic deletion (Ex10-12) in 2 European men, 2 missense variants in 2 European/German men, and 3 splice variants in two white and one Arabic men.

ii) PMID: 29661171 (2018)- a novel hemizygous missense variant (W856C) in two brothers with azoospermia (absent in the mother- ?can it be gonadal mosaicism). Their testicular biopsy revealed meiotic arrest and no post-meiotic round spermatids and mature spermatozoa were observed.

iii) PMID: 34621296 (2021)- seven novel hemizygous variants in three familial (one missense, two splice) and four NOA-affected sporadic (three frameshift, one nonsense) cases

iv) PMID: 37124723 (2023)- three novel hemizygous variants ( p.R105*, p.K143Q, and p.G859R) in three unrelated NOA males and their histological analysis of testicular biopsy specimens revealed thicker basement membrane of the seminiferous tubules and poorly developed spermatocytes.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 SPAG6 Jasmine Chew gene: SPAG6 was added
gene: SPAG6 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SPAG6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPAG6 were set to 35232447; 38073178; 32124190
Phenotypes for gene: SPAG6 were set to MONDO:0004983
Review for gene: SPAG6 was set to GREEN
Added comment: i) PMID: 35232447- two homozygous variants (F1 II-1: p. A103D; F2 II-1:p. K196Sfs*6) in two unrelated Han Chinese men with nonsyndromic asthenoteratozoospermia with severe multiple morphological abnormalities of the sperm flagella. Immunostaining and WB showed lower SPAG6 expression in spermatozoa of both affected males. The couple with the missense variant as able to conceive successfully after undergoing ICSI.
ii) PMID: 38073178- a homozygous missense p.R310W in three brothers (two brothers with both asthenozoospermia and oligozoospermia, third brother with azoospermia)
iii) PMID: 32124190- a novel compound heterozygous variant (c.143_145del: p.48_49del, c.585delA: p.Lys196Serfs*6) in an infertile PCD patient with severe with asthenoteratozoospermia, presented with morphological defects of sperm flagella and lower mRNA and protein expression in mutant sperms.
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 SEPT12 Jasmine Chew gene: SEPT12 was added
gene: SEPT12 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: SEPT12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SEPT12 were set to 22479503; 22275165; 35547809
Phenotypes for gene: SEPT12 were set to #MIM:614822
Review for gene: SEPT12 was set to GREEN
Added comment: i) PMID: 22479503- A homozygous truncating variant (c.474 G>A) in 15 unrelated infertile men and 9 of them had teratozoospermia (88 to 99% of abnormal sperm);Transfection studies also showed that the mutant SEPT12 disrupted filament formation of wildtype SEPT12 in a dose-dependent manner.
ii) PMID:22275165- Two heterozygous missense variants (T89M and D197N) in a man with asthenoteratozoospermia and another man with oligoasthenozoospermia. Functional analysis demonstrated that both mutations adversely affected filament formation of wildtype SEPT12 in a dose-dependent manner.
iii) PMID: 35547809- A heterozygous missense variant (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). Their Septin12 knockout mice study also showed that Septin12 -/- male mice are infertile with reduced sperm counts and abnormal sperm morphology but male Septin12 +/− mice are fertile. This observation contradicted with the previous studies showed that male Septin12 +/− chimeric mice are infertile (Lin et al., 2009, PMID: 19359518). The main difference is that the Septin12 +/− chimeric mice were generated in Lin et al., 2009 (PMID: 19359518) was by blastocyst injection of Septin12 +/− embryonic stem cells (ESCs), while their Septin12 +/− founder mice were established by CRISPR/Cas9 mediated gene editing in the zygote. The quality of injected Septin12 +/− ESCs might affect the experimental result.

Note:#MIM:614822 stated as AD, but there's evidence suggesting AR
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 PLCZ1 Jasmine Chew changed review comment from: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature; to: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 PLCZ1 Jasmine Chew changed review comment from: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593 (2023)- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249 (2023)- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature; to: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 PLCZ1 Jasmine Chew gene: PLCZ1 was added
gene: PLCZ1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: PLCZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCZ1 were set to 26721930; 31463947; 36593593; 37004249
Phenotypes for gene: PLCZ1 were set to #MIM:617214
Review for gene: PLCZ1 was set to GREEN
Added comment: i) PMID:26721930- homozygous missense variant (I489F) in 2 Tunisian brothers with infertility due to oocyte activation failure.
ii) PMID:31463947- 3 homozygous variants (C196X, S350P, L246F) in 4 Chinese men from 3 consanguineous families with SPGF17 and total fertilization failure of oocytes after intracytoplasmic sperm injection.
iii) PMID: 36593593 (2023)- compound heterozygosity for splice site and missense variants (c.1174+3A-C and N425S in case 2; c.136-1G-C and G453D in case 3) in 2 unrelated Chinese men with infertility due to acrosomal abnormalities and total fertilization failure.
iv) PMID: 37004249 (2023)- previously reported homozygous variant (C196X) in two unrelated men with infertility due to total fertilization failure
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 EXO1 Jasmine Chew gene: EXO1 was added
gene: EXO1 was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: EXO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EXO1 were set to 39595984; 32772095; 36385415
Phenotypes for gene: EXO1 were set to MONDO:0005387
Review for gene: EXO1 was set to GREEN
Added comment: 1. PMID:39595984- heterozygous nonsense variant (p.Glu829Ter) in an European female with diminished ovarian reserve
2. PMID:32772095- heterozygous missense variant (p.Thr52Ser) in a Chinese patient with POI, which impaired the meiotic process in budding yeast cells and analysis of transfected HEK293 cells demonstrated impaired efficiency of homologous recombination repair for DNA double-stranded breaks with the mutant compared to wildtype EXO1
3. PMID:36385415- heterozygous nonsense variant (p.Tyr742Ter) in a case (C23) with recurrent pregnancy loss (RPL), primary infertility (PI), recurrent implantation failure (RIF)
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 DDX3Y Jasmine Chew changed review comment from: PMID:36997603- 4 (3 German, 1 Estonian) unrelated men with non-obstructive azoospermia carrying different LOF variants- absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain, and are predicted to lead to degradation of the transcripts by nonsense-mediated decay. All four patients shared histological phenotype of Sertoli cell-only (SCO), reduced testicular volume, and had elevated FSH upon primary or later presentation indicative of spermatogenic failure.

Mode of inheritance: Y-linked
Sources: Literature; to: PMID:36997603- Four (3 German, 1 Estonian) unrelated men with non-obstructive azoospermia carrying different LOF variants- absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain, and are predicted to lead to degradation of the transcripts by nonsense-mediated decay. All four patients shared histological phenotype of Sertoli cell-only (SCO), reduced testicular volume, and had elevated FSH upon primary or later presentation indicative of spermatogenic failure.

Mode of inheritance: Y-linked
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 DDX3Y Jasmine Chew gene: DDX3Y was added
gene: DDX3Y was added to Infertility and Pregnancy Loss. Sources: Literature
Mode of inheritance for gene: DDX3Y was set to Other
Publications for gene: DDX3Y were set to 36997603
Phenotypes for gene: DDX3Y were set to MONDO:0100459
Review for gene: DDX3Y was set to GREEN
Added comment: PMID:36997603- 4 (3 German, 1 Estonian) unrelated men with non-obstructive azoospermia carrying different LOF variants- absent in the gnomAD database (v2.1.1), abrogate at least the sequence of the C-terminal helicase domain, and are predicted to lead to degradation of the transcripts by nonsense-mediated decay. All four patients shared histological phenotype of Sertoli cell-only (SCO), reduced testicular volume, and had elevated FSH upon primary or later presentation indicative of spermatogenic failure.

Mode of inheritance: Y-linked
Sources: Literature
Infertility and Recurrent Pregnancy Loss v0.0 Zornitza Stark Added Panel Infertility and Pregnancy Loss