Variations of C14ORF39 and SYCE1 identified in idiopathic premature ovarian insufficiency and nonobstructive azoospermia

Context Premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) are the most sever disease causing irreversible infertility in female and male respectively. The contribution of synaptonemal complex (SC) genes variations in the pathogenesis of sporadic patients with POI and NOA has not been systematically illustrated. Objective To investigate the role of SC genes in the pathogenesis of sporadic POI and NOA. Design Genetic and functional study. Setting University-based reproductive medicine center. Patient(s) A total of 1,030 patients with sporadic POI and 400 patients with sporadic NOA. Intervention(s) The variations of SC genes were filtered in the in-house database of whole exome sequencing performed in 1,030 patients with sporadic POI and 400 patients with sporadic NOA. The pathogenic or likely pathogenic variations following recessive inheritance mode were selected according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed by Sanger sequencing. The pathogenic effects of the variations were verified by functional studies. Main Outcome Measure(s) ACMG classification and functional characteristics. Result(s) Two homozygous variations of C14ORF39 and two recessive variations of SYCE1 were firstly identified in sporadic patients with POI and NOA respectively. Functional studies showed the C14ORF39 variations significantly accelerated the protein degradation, and the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis. Conclusion(s) Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function.

A pathogenic DMC1 frameshift mutation causes nonobstructive azoospermia but not primary ovarian insufficiency in humans

Nonobstructive azoospermia (NOA) and diminished ovarian reserve (DOR) are two disorders that can lead to infertility in males and females. Genetic factors have been identified to contribute to NOA and DOR. However, the same genetic factor that can cause both NOA and DOR remains largely unknown. To explore the candidate pathogenic gene that causes both NOA and DOR, we conducted whole-exome sequencing (WES) in a non-consanguineous family with two daughters with DOR and a son with NOA. We detected one pathogenic frameshift variant (NM_007068:c.28delG, p. Glu10Asnfs*31) following a recessive inheritance mode in a meiosis gene DMC1 (DNA meiotic recombinase 1). Clinical analysis showed reduced antral follicle number in both daughters with DOR, but metaphase II oocytes could be retrieved from one of them. For the son with NOA, no spermatozoa were found after microsurgical testicular sperm extraction. A further homozygous Dmc1 knockout mice study demonstrated total failure of follicle development and spermatogenesis. These results revealed a discrepancy of DMC1 action between mice and humans. In humans, DMC1 is required for spermatogenesis but is dispensable for oogenesis, although the loss of function of this gene may lead to DOR. To our knowledge, this is the first report on the homozygous frameshift mutation as causative for both NOA and DOR and demonstrating that DMC1 is dispensable in human oogenesis.