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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 | 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 | 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 v0.82 | 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 | 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 v0.77 | 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 | 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 v0.64 | AIRE | Zornitza Stark Marked gene: AIRE as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.64 | AIRE | Zornitza Stark Gene: aire has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.64 | AIRE | Zornitza Stark Classified gene: AIRE as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.64 | AIRE | Zornitza Stark Gene: aire has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Infertility and Recurrent Pregnancy Loss v0.63 | 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 | PDCD2 |
Jasmine Chew gene: PDCD2 was added gene: PDCD2 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: PDCD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDCD2 were set to 40208938 Phenotypes for gene: PDCD2 were set to Non-immune hydrops fetalis, MONDO:0009369; Recurrent pregnancy loss susceptibility, MONDO:0000144 Review for gene: PDCD2 was set to AMBER Added comment: PMID: 40208938- Novel biallelic PDCD2 variants associated with hydrops fetalis and early pregnancy loss in two affected families. Family 1 with RPL had three fetuses with NIHF who were all homozygous for p.(Pro28Ser) in PDCD2, while Family 2 had p.(Pro28Ser) in trans with p.(Arg34Pro) in two fetuses with NIHF. Family 2 was additionally notable for having a healthy child who was homozygous for the reference allele, consistent with appropriate disease segregation with the PDCD2 variants. Functional studies using primary fetal fibroblasts and human cell lines for both variants showed reduced PDCD2 mRNA level in affected patients' fibroblasts, reduced cellular accumulation of mutant proteins with impaired ability to associate with the 40S subunit ribosomal protein uS5, and further depletion of PDCD2 in fibroblast cells severely impacted ribosome biogenesis. It is notable that formation of the PDCD2-uS5 complex was not completely abolished by the patient variants and that rRNA processing was only partially impaired, as indicated by levels of 40S pre-rRNAs. We thus suspect that the PDCD2 pathogenic variants p.(Pro28Ser) and p.(Arg34Pro) are hypomorphic alleles, with a low level of residual function allowing for cellular differentiation and growth to a certain extent. Sources: Literature |
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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 | 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 v0.18 | 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 | 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 | 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 v0.12 | RXFP2 |
Jasmine Chew changed review comment from: i) PMID: 39222519 (2024)- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism. ii) PMID: 37208861 (2023)- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies). iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay. Note: couldn't access MONDO # as website down (phenotypes to be updated) Sources: Literature; to: i) PMID: 39222519- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism. ii) PMID: 37208861- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies). iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay. Note: couldn't access MONDO # as website down (phenotypes to be updated) Sources: Literature |
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| Infertility and Recurrent Pregnancy Loss v0.12 | RXFP2 |
Jasmine Chew gene: RXFP2 was added gene: RXFP2 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: RXFP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RXFP2 were set to 39222519; 37208861; 38430325 Review for gene: RXFP2 was set to GREEN Added comment: i) PMID: 39222519 (2024)- a compound heterozygous variant (intragenic deletion of exon 1-5 and missense variant p.Glu77Lys) in a family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism. The Glu77Lys mutant showed no cAMP activity and hence failed to signal in response to INSL3, confirming a loss-of-function mechanism. ii) PMID: 37208861 (2023)- Homozygous LOF (p.Phe469Serfs*8) and missense (p.Asn339Asp) variants in two unrelated infertile man with impaired spermatogenesis. The missense variant primarily impacts cell surface expression of the protein which directly correlates with reduced INSL3 activation (following protein expression studies). iii) PMID: 38430325 - a homozygous non-canonical splicing variant (NM_130806: c.1376-12A > G) in a case with cryptorchidism and NOA, which was confirmed to cause aberrant splicing of exons 15 and 16, leading to an abnormal transcript initiation and a frameshift using minigene assay. Note: couldn't access MONDO # as website down (phenotypes to be updated) Sources: Literature |
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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 v0.0 | EXO1 |
Jasmine Chew gene: EXO1 was added gene: EXO1 was added to Infertility and Pregnancy Loss. Sources: Literature Mode of inheritance for gene: EXO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EXO1 were set to 39595984; 32772095; 36385415 Phenotypes for gene: EXO1 were set to MONDO:0005387 Review for gene: EXO1 was set to GREEN Added comment: 1. PMID:39595984- heterozygous nonsense variant (p.Glu829Ter) in an European female with diminished ovarian reserve 2. PMID:32772095- heterozygous missense variant (p.Thr52Ser) in a Chinese patient with POI, which impaired the meiotic process in budding yeast cells and analysis of transfected HEK293 cells demonstrated impaired efficiency of homologous recombination repair for DNA double-stranded breaks with the mutant compared to wildtype EXO1 3. PMID:36385415- heterozygous nonsense variant (p.Tyr742Ter) in a case (C23) with recurrent pregnancy loss (RPL), primary infertility (PI), recurrent implantation failure (RIF) Sources: Literature |
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