Abstract
Premature ovarian insufficiency (POI) is defined as depletion of ovarian function before 40 years of age, which affects 3.7% of women in reproductive age. The etiology of POI is heterogeneous. Recently, with the widespread use of whole-exome sequencing (WES), the DNA repair genes, especially for those involved in meiosis progress, were enriched in the causative gene spectrum of POI. In this study, through the largest in-house WES database of 1,030 patients with sporadic POI, we identified two novel homozygous variations in HSF2BP (c.382T>C, p.C128R; c.557T>C, p.L186P). An in vitro functional study revealed that both variations impaired the nuclear location of HSF2BP and affected its DNA repair capacity. Our studies highlighted the essential role of meiotic homologous recombination genes in the pathogenesis of sporadic POI.
Highlights
Premature ovarian insufficiency (POI) is defined by depletion of ovarian function before the age of 40 years, characterized by amenorrhea or oligomenorrhea and elevated serum level of folliclestimulating hormone (FSH) (Webber et al, 2016)
The variants were classified as pathogenic (P), likely pathogenic (LP), or variations of uncertain significance (VUS) according to the guidelines proposed by the American College of Medical Genetics and Genomics (ACMG) (Richards et al, 2015)
Through variation screening in the in-house whole-exome sequencing (WES) database of sporadic POI, eight variations in HSF2BP (GenBank: NM_007031.2) have been identified
Summary
Premature ovarian insufficiency (POI) is defined by depletion of ovarian function before the age of 40 years, characterized by amenorrhea or oligomenorrhea and elevated serum level of folliclestimulating hormone (FSH) (Webber et al, 2016). A recent meta-analysis found that 3.7% of women before 40 years of age are affected by POI (Golezar et al, 2019). Autoimmune disease, and iatrogenic factors account for nearly 50% of the patients, with the remaining half of the cases being idiopathic (Vujovic, 2009; De Vos et al, 2010). 20% of the cases have first- or second-degree relatives with POI. Genetic disorder is an indispensable factor in POI pathogenesis (Qin et al, 2015). The contribution of those genes in sporadic cases was rarely reported
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