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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 - Unpublished in-house data/observation: A heterozygous deletion with a breakpoint in ZNF597 was observed in the female partner of a couple experiencing x4 early pregnancy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 v0.103 | 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 | BLM |
Jasmine Chew gene: BLM was added gene: BLM was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BLM were set to 34794894; 29056561; 28846287 Phenotypes for gene: BLM were set to Bloom syndrome, MIM# 210900 Review for gene: BLM was set to GREEN Added comment: PMID: 28846287 (Gene Review)- Women may be fertile but often have early menopause, and men tend to be infertile. Most men with BSyn assessed for infertility have had azoospermia or severe oligospermia. PMID: 35671666, PMID: 24858046- BLM physically interacts with MUS81, an endonuclease involved in the restart of stalled replication forks and HR repair. Loss of Mus81 in Blm hypomorph mutant mice leads to infertility, and growth and developmental defects that are not observed in single mutants. Double mutant cells and mice were hypersensitive to Mitomycin C and γ-irradiation (IR) compared with controls and their repair of DNA double-strand breaks (DSBs) mediated by HR pathway was significantly defective, whereas their non-homologous-end-joining repair was elevated compared with controls. Sources: Literature |
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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 v0.77 | 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 | 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 | 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 | MEI1 |
Jasmine Chew changed review comment from: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA) New papers (biallelic variants for OZEMA): i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles. ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. New papers (biallelic variants for NOA): i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. - others- PMID: 32741963, PMID: 36017582 Note: Moderate evidence for OZEMA and HM in FeRGI database Sources: Literature; to: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA) New papers (biallelic variants for OZEMA): i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles. ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. New papers (biallelic variants for NOA): i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. - others: PMID: 32741963;36017582 Note: Moderate evidence for OZEMA and HM in FeRGI database Sources: Literature |
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| Infertility and Recurrent Pregnancy Loss v0.77 | MEI1 |
Jasmine Chew gene: MEI1 was added gene: MEI1 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: MEI1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MEI1 were set to 30388401 Phenotypes for gene: MEI1 were set to Recurrent hydatidiform mole 3, MIM# 618431; Non-obstructive azoospermia Review for gene: MEI1 was set to GREEN Added comment: Literature in OMIM- PubMed: 30388401- biallelic variants in two women with history of RPL and HM (probands 1333 and 880) and affected family members (females with similar phenotypes and also male with NOA) New papers (biallelic variants for OZEMA): i) PMID: 38416203- novel compound heterozygous frameshift variants (c.3002delC and c.2264_2268 + 11delGTGAGGTATGGACCAC) in a case of a female infertile patient suffering from embryonic arrest and recurrent implantation failure. Her arrested embryos from MEI1-affected oocytes exhibited abnormalities in copy number variation and DNA methylation following CMA, which contrasts with the proliferating embryos secondary to the loss of maternal chromosomes in hydatidiform moles. ii)PMID: 34037756- five novel mutations in MEI1 in nine patients with similar infertile phenotypes of recurrent hydatidiform moles, embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss from seven independent families. In vitro studies also demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1. New papers (biallelic variants for NOA): i) PMID: 36759719- Biallelic deleterious variants in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. - others- PMID: 32741963, PMID: 36017582 Note: Moderate evidence for OZEMA and HM in FeRGI database Sources: Literature |
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| Infertility and Recurrent Pregnancy Loss v0.76 | MOS | Zornitza Stark Marked gene: MOS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.76 | MOS | Zornitza Stark Gene: mos has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.76 | MOS | Zornitza Stark Classified gene: MOS as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.76 | MOS | Zornitza Stark Gene: mos has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.63 | 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 | 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 | 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 | 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 | TRIP13 |
Jasmine Chew gene: TRIP13 was added gene: TRIP13 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRIP13 were set to 32473092; 28553959; 35812326 Phenotypes for gene: TRIP13 were set to Oocyte/zygote/embryo maturation arrest 9, #MIM 619011; Mosaic variegated aneuploidy syndrome 3, #MIM 617598 Review for gene: TRIP13 was set to GREEN Added comment: Literature in OMIM- PMID: 32473092;28553959- different biallelic variants in >3 unrelated affected individuals New papers: i) PMID: 35812326- Two women with zygotic cleavage failure (ZCF) carrying homozygous p. Glu381Lys and compound heterozygous p. Lys420Glu and p. His26Arg. All three variants resulted in obvious changes in hydrogen bonding and consistent increase in DNA damage. Additionally, transcriptomic sequencing of oocytes and arrested embryos containing these variants suggested a greater number of differentially expressed transcripts in germinal vesicle (GV) oocytes than in 1-cell embryos. Sources: Literature |
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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 v0.18 | 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 | 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 | 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 v0.12 | SYCP3 |
Jasmine Chew gene: SYCP3 was added gene: SYCP3 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: SYCP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SYCP3 were set to 14643120; 19110213 Phenotypes for gene: SYCP3 were set to Spermatogenic failure 4, Recurrent pregnancy loss 4, MIM# 270960 Review for gene: SYCP3 was set to GREEN Added comment: Spermatogenic failure 4, MIM# 270960 i) PMID: 14643120- identified a heterozygous 1-bp deletion (643delA) in 2 unrelated patients with azoospermia with with maturation arrest , resulting in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the protein. The mutant protein showed greatly reduced interaction with the wildtype protein in vitro and interfered with SYCP3 fiber formation in cultured cells. The results suggested that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein by dominant-negative interference. Pregnancy loss, recurrent, 4, MIM# 270960 i) PMID: 19110213- identified a heterozygous deletion and a point variant (-16delACTT in intron 7 and 657T-C transition at the last nucleotide of exon 8) in 2 of the women with recurrent pregnancy loss that were not found in 150 fertile women. Both mutant proteins were shown to inhibit normal fiber formation of SYCP3 when coexpressed in a heterologous system. This suggested that the heterozygous variants are likely to form aberrant lateral elements in the synaptonemal complex in a dominant-negative manner, possibly leading to abnormal chromosomal behavior in meiosis I during oogenesis that might lead to recurrent miscarriage. Also noted that the SYCP3-related phenotype in humans, in which affected males are infertile whereas affected females have recurrent pregnancy loss, is similar to that seen in Sycp3-deficient mice (Yuan et al., 2000; Yuan et al., 2002). Sources: Literature |
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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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