Genetic etiologic analysis in 74 Chinese Han women with idiopathic premature ovarian insufficiency by combined molecular genetic testing.

Purpose To identify the disease-causing genes of Chinese Han women with idiopathic premature ovarian insufficiency (POI). Methods Seventy-four Chinese Han women with idiopathic POI were collected to analyze the genetic etiology. Triplet repeat-primed polymerase chain reaction (TP-PCR) was performed to screen the FMR1 (CGG)n premutation, and then 60 POI-related genes were sequenced by targeted next-generation sequencing (NGS) in POI patients with normal FMR1. Results A total of one patient (1/74) with FMR1 premutation was identified. Targeted NGS revealed that 15.07% (11/73) patients had pathogenic or likely pathogenic variants of Mendelian genes (FOXL2, EIF2B2, CYP17A1, CLPP, MCM9, GDF9, MSH5, ERCC6, POLG). Ten novel variants in six Mendelian genes were identified, such as CLPP c.355A>C (p.I119L) and c.688A>C (p.M230L), MCM9 c.1157C>T (p.T386M) and c.1291A>G (p.M431V), GDF9 c. 238C>T (p.Q80X), MSH5 c.604G>C (p.G202R) and c.2063T>C (p.I688T), ERCC6 c.C1769C>T (p.P590L), POLG c.2832G>C (p.E944D), and c.2821A>G (p.I941V). Conclusion This study suggested targeted NGS was an efficient etiologic test for idiopathic POI patients without FMR1 premutation and enriched the variant spectrum of POI-related genes.