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| 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 - Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy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 |
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| 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 v0.151 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.63 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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. |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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