scholarly journals STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia

2020 ◽  
Vol 26 (9) ◽  
pp. 665-677
Author(s):  
Sylvie Jaillard ◽  
Kenneth McElreavy ◽  
Gorjana Robevska ◽  
Linda Akloul ◽  
Farah Ghieh ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Genetic Basis ◽  
Missense Variant ◽  
Reproductive Organs ◽  
Female Infertility ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Male And Female ◽  
Whole Exome ◽  
Pathological Development

Abstract Infertility, a global problem affecting up to 15% of couples, can have varied causes ranging from natural ageing to the pathological development or function of the reproductive organs. One form of female infertility is premature ovarian insufficiency (POI), affecting up to 1 in 100 women and characterised by amenorrhoea and elevated FSH before the age of 40. POI can have a genetic basis, with over 50 causative genes identified. Non-obstructive azoospermia (NOA), a form of male infertility characterised by the absence of sperm in semen, has an incidence of 1% and is similarly heterogeneous. The genetic basis of male and female infertility is poorly understood with the majority of cases having no known cause. Here, we study a case of familial infertility including a proband with POI and her brother with NOA. We performed whole-exome sequencing (WES) and identified a homozygous STAG3 missense variant that segregated with infertility. STAG3 encodes a component of the meiosis cohesin complex required for sister chromatid separation. We report the first pathogenic homozygous missense variant in STAG3 and the first STAG3 variant associated with both male and female infertility. We also demonstrate limitations of WES for the analysis of homologous DNA sequences, with this variant being ambiguous or missed by independent WES protocols and its homozygosity only being established via long-range nested PCR.

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

2018 ◽  
Vol 55 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Wen-Bin He ◽  
Chao-Feng Tu ◽  
Qiang Liu ◽  
Lan-Lan Meng ◽  
Shi-Min Yuan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Male Patient ◽  
Histological Analysis ◽  
Pedigree Analysis ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Causative Gene ◽  
Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

scholarly journals Heterozygous FMN2 Missense Variant Found in A Family Case of Premature Ovarian Insufficiency

2021 ◽  
Author(s):  
Jie Li ◽  
Tianliu Peng ◽  
Le Wang ◽  
Panpan Long ◽  
Ruping Quan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Low Frequency ◽  
Missense Variant ◽  
Sporadic Case ◽  
Premature Ovarian Insufficiency ◽  
Chinese Family ◽  
Ovarian Insufficiency ◽  
Mutant Type ◽  
Pathogenic Genes ◽  
Whole Exome

Abstract Background Premature Ovarian Insufficiency plagues 1% of women under 40, while quite a few remain an unknown cause. The development of sequencing has helped find pathogenic genes and reveal the relationship between DNA repair and ovarian reserve. Through the exome sequencing, our study targets screening out the possible POI pathogenic gene and variants in a Chinese family and 20 sporadic POI patients, preliminarily exploring the functional impact and finding out potential linkages between the gene and POI. Results The whole exome sequencing suggested a novel FMN2 heterozygous variant c.1949C > T (p.Ser650Leu) carried by all three patients in a Chinese family and another c.1967G > A(p.Arg656His) variant in a sporadic case. Since no FMN2 missense mutation is reported for causing human POI, we preliminarily assessed p.Ser650Leu variant via cross-species alignment and 3D modeling and found it possibly deleterious. A series of functional evidence was consistent with our hypothesis. We proved the expression of FMN2 in different stages of oocytes and observed a statistical difference of chromosomal breakages between the POI patient carrying p.Arg656His variant and the health control (p = 0.0013). Western Blot also suggested a decrease in FMN2 and P21 in the mutant type and an associated increase in H2AX. The p.Arg656His variant with an extremely low frequency also indicated that the gene FMN2 might play an essential role in the genetic etiology of POI. To the best of our knowledge, this is the first POI report on missense variants of FMN2. Conclusion This finding indicates a novel gene possibly related to POI and sheds lights on the study of FMN2.

Genetic Basis of Male and Female Infertility

2017 ◽  
pp. 1-16 ◽  
Author(s):  
Rathika Mallepaly ◽  
Peter R. Butler ◽  
Amin S. Herati ◽  
Dolores J. Lamb
Keyword(s):  
Genetic Basis ◽  
Female Infertility ◽  
Male And Female

scholarly journals A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Natalia Felipe-Medina ◽  
Sandrine Caburet ◽  
Fernando Sánchez-Sáez ◽  
Yazmine B Condezo ◽  
Dirk G de Rooij ◽  
...  
Keyword(s):  
Missense Variant ◽  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Knock Out ◽  
Recombination Nodules ◽  
Hypomorphic Allele ◽  
Whole Exome ◽  
Gene Functional Analysis ◽  
Knock Out Mouse

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. 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. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.

scholarly journals Homozygous variants in SYCP2L cause premature ovarian insufficiency

2020 ◽  
pp. jmedgenet-2019-106789 ◽  
Author(s):  
Wen-Bin He ◽  
Chen Tan ◽  
Ya-Xin Zhang ◽  
Lan-Lan Meng ◽  
Fei Gong ◽  
...  
Keyword(s):  
Bioinformatic Analysis ◽  
Female Infertility ◽  
Premature Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Genetic Causes ◽  
Functional Characterisation ◽  
Whole Exome ◽  
Functional Analyses

BackgroundThe genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown.ObjectiveTo identify the genetic causes of POI in 110 patients.MethodsWhole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants.ResultsWe identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function.ConclusionsSYCP2L is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility.

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

scholarly journals A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

2017 ◽  
Vol 176 (5) ◽  
pp. K9-K14 ◽  
Author(s):  
Sandrine Caburet ◽  
Ronit Beck Fruchter ◽  
Bérangère Legois ◽  
Marc Fellous ◽  
Stavit Shalev ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Polycystic Ovary ◽  
Missense Variant ◽  
Genetic Alterations ◽  
Homozygous Mutation ◽  
Gonadotropin Secretion ◽  
Whole Exome ◽  
A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

scholarly journals A comprehensive genetic assessment of male and female infertility using next-generation sequencing

2017 ◽  
Vol 108 (3) ◽  
pp. e240
Author(s):  
G.R. Kellogg ◽  
A. Pollock ◽  
R. Shraga ◽  
S. Parets ◽  
B. Patel ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Female Infertility ◽  
Next Generation ◽  
Male And Female ◽  
Genetic Assessment ◽  
Generation Sequencing

scholarly journals Sterility in breeding sows as a consequence of reproductive tract diseases

2002 ◽  
Vol 56 (1-2) ◽  
pp. 105-110
Author(s):  
Radoslav Dosen ◽  
Mladen Gagrcin ◽  
Jasna Prodanov
Keyword(s):  
Transport Process ◽  
Reproductive Tract ◽  
Reproductive Organs ◽  
Pathological Changes ◽  
Ovarian Insufficiency ◽  
Fertilization Process ◽  
Pathological Conditions

In this paper we examined the effects of certain pathological conditions on the sterility of breeding sows. Pathomorphological investigations were performed on 185 reproductive organs. We analyzed the reasons for elimination from local records. The biggest number of sows with pathological changes on reproductive organs were in the group of barren sows, 48.68% followed by anestric sows, 30.26%, and the smallest number in sows with failed fertilizations, 21.05%. Cysts in ovaries, ovarian tubes, oviducts and ?the mesosalpinx were found in 23.77% of the examined sows. Lutein cysts were found in a significantly higher percentage in sows which fail to be fertilized than in barren or anestric animals. Small granular degeneration of the ovaries was determined in barren sows and those which cannot be fertilized, while it was not determined in anestric sows. Cysts on uterus ligaments and ovaries and on ovarian tubes and oviducts were found in significantly higher numbers in sows which fail be fertilized than in barren or anestric sows. Their presence can be connected to obstructions in the transport process of spermatozoa, eggs, and the fertilization process in sows which fail to be fertilized, especially in cases of cysts located on the very serosa of ovarian tubes which we found in these sows. We determined small granular degeneration of the ovaries in barren sows and those which fail to fertilized, but not in anestric sows. Ovarian insufficiency was mostly connected to anestric sows. Vaginitis, endometritis, periometritis and oocytis present an important factor in the occurrence of sterility primarily in sows which are barren or which fail to be fertilized.

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