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.

Keywords: ERCC6; adolescents; heterozygous variant; premature ovarian insufficiency.

FIGURE 1

Identification of a heterozygous ERCC6 variant in a Chinese family with non‐syndromic POI. (a) Pedigree of the POI family. The proband was represented with a black arrow. (b) Sanger sequencing validation of the identified heterozygous ERCC6 variant in the family. NA, DNA samples were not available; W, wild type; M, mutant. The red arrow indicated the position of the ERCC6 variant

FIGURE 2

Analysis of the identified ERCC6 variant. (a) Schematic diagram of ERCC6 transcript NM_000124.4. Exons of ERCC6 were represented with rectangles. The blue and blank regions indicated the coding and non‐coding regions of exons, respectively. The variant lay in exon 13 of ERCC6 indicated by the red arrow. (b) Alignment of ERCC6 amino acid sequence amongst species. The variant G815D was highly conserved across different species. Sequences used were as follows: Homo sapiens, NP_000115.1; Pan troglodytes, XP_009438633.3; Bos taurus, NP_001178272.1; Mus musculus, NP_001074690.1; Rattus norvegicus, NP_001100766.1; Gallus gallus, XP_004942197.2; Danio rerio, XP_688972.2. (c) Schematic illustration of ERCC6 protein. The yellow and blue rectangles represented ATPase domain and Ubiquitin‐binding domain (UBD) of ERCC6 protein (NP_000115.1), respectively. Green and grey rectangles in an ERCC6‐PGBD3 fusion protein (NP_001263988.1) represented the exons 1–5 of ERCC6 and PGBD3, respectively. Numbers refer to amino acid positions. The red and black arrows indicated the position of the ERCC6 variant identified in this study and previously reported, respectively

FIGURE 3

3D structure modelling of wild type and mutant ERCC6 protein. (a) In the wild type ERCC6 protein, G815 had no H‐bond with adjacent P816 and K817 residues. (c) In the mutant ERCC6 protein, the amino acid residue at 815 was supposed to form H‐bonds with P816 and K817 when substituted by Asp. (b) and (d) displayed magnification of the region within red dashed boxes in (a) and (c), respectively. The H‐bond was indicated by green dotted lines