Dataset Information

A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.

ABSTRACT:

Background

Premature ovarian insufficiency (POI) is a clinical syndrome occurring in women before 40 with decreased ovarian function. Up to 25% of POI cases result from genetic factors that remain largely unknown. The Excision repair cross-complementing, group 6 (ERCC6) variant has been found to cause POI, which is hardly ever diagnosed in adolescents.

Methods

Whole-exome sequencing was performed on a 19-year-old proband with non-syndromic POI and her parents. Sanger sequencing was used to confirm the identified variant. The effect of the variant on the protein was analyzed in silico and Swiss-MODEL.

Results

A novel heterozygous missense variant, c.2444G > A (p. GLy815Asp) of ERCC6 was identified in the proband who inherited the variant from her father. The variant was confirmed in another POI patient from the pedigree and was absent in the proband's mother and sister who presented normally. In silico analysis predicted this variant was deleterious. Swiss-Model revealed that the mutant amino acid formed multiple H-bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein.

Conclusion

We firstly diagnosed an adolescent POI case associated with a novel heterozygous ERCC6 variant. The results expanded the variants spectrum of ERCC6 and provided guidance for POI diagnosis and genetic counselling.

SUBMITTER: Kuang L

PROVIDER: S-EPMC9544206 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.

Kuang Lele L Liu Bin B Xi Di D Gao Yuping Y

Molecular genetics & genomic medicine 20220816 10

<h4>Background</h4>Premature ovarian insufficiency (POI) is a clinical syndrome occurring in women before 40 with decreased ovarian function. Up to 25% of POI cases result from genetic factors that remain largely unknown. The Excision repair cross-complementing, group 6 (ERCC6) variant has been found to cause POI, which is hardly ever diagnosed in adolescents.<h4>Methods</h4>Whole-exome sequencing was performed on a 19-year-old proband with non-syndromic POI and her parents. Sanger sequencing wa ...[more]

PMID: 35975393

Similar Datasets

Project description:BackgroundPremature ovarian insufficiency (POI) is a severe disorder of female infertility, characterized by 4-6 months of amenorrhea before the age of 40 years, with elevated follicle stimulating hormone (FSH) levels (> 25 IU/L). Although several genes have been reported to contribute to the genetic basis of POI, the molecular mechanism of POI remains unclear.MethodsWhole-exome sequencing (WES) was performed. Sanger sequencing was carried out to validate the variant in the proband and her mother. In silico algorithms were used to analyze the mutational effect of the variant. Protein 3D structural modeling was used for predicting mutated protein structures. Vector construction and plasmids transfection were performed, and subsequently RNA-sequencing (RNA-seq) was carried out in each group to dissect the differentially expressed genes in wild-type (WT) and D1853H NOTCH2 mutant expressing groups. Gene Ontology analysis was also used to analyze the enriched biological processes or pathways among the differentially expressed genes.ResultsWe report two non-syndromic POI patients from a Chinese pedigree. The FSH level of the proband (the daughter) was 46 IU/L at the age of 22. Her menarche was at the age of 12, but she was amenorrhea at the age of 20. By WES, a rare heterozygous variant (c.5557G > C;p.D1853H) in the NOTCH2 gene was identified. In silico analysis suggested that p.D1853H was a pathogenic allele. Protein 3D structural modeling suggested that D1853H may enhance or weaken the electrostatic surface potential. By molecular analysis, we found that cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. However, 106 protein-coding genes were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells, and these genes were enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones, revealing a unknown underlying mechanism of the pathology that leads to POI.ConclusionsWe conclude that the rare heterozygous variant in NOTCH2 may be associated with POI. This finding provides researchers and clinicians with a better understanding of the etiology, molecular mechanism and genetic consulting of POI.

Dataset Information

A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.

Background

Methods

Results

Conclusion

Publications

A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.

Similar Datasets

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