RF34 | PMON203 Copy Number Variant Analysis Reveals Novel Candidate Genes Associated with Primary Ovarian Insufficiency

: Primary ovarian insufficiency (POI) is characterized by a heterogeneous genetic background. Moreover, the etiology of most POI cases remains unclear. Herein, our goal was to investigate the presence of rare deletions or duplications in patients presenting with POI, which could lead to identification of novel chromosomal regions and/or genes potentially associated with disease risk. PATIENTS AND METHODS: Sixty-six patients presenting idiopathic POI were evaluated; 44 had primary amenorrhea and 22 secondary amenorrhea. Chromosomal microarray analysis was performed to detect copy number variants (CNVs) using array-CGH or SNP-array. Identified CNVs were validated by population databases of either health individuals (Database of Genomic Variants - DGV) or patients carrying chromosomal structural alterations (DECIPHER). A set of rare CNVs was selected and annotated in regard to gene content and clinical associations using bioinformatic tools (RefSeq, OMIM, PubMed, Ovarian Kaleidoscope Database, and Mouse Genome Informatics). RESULTS: Fifteen rare CNVs were found in 13 patients, ten of them with primary amenorrhea. The identified CNVs comprised four deleted and 11 duplicated regions, in which the break points occurred intragenic in 8 of them. Most of the CNVs were mapped in the autosomes. Seven CNVs identified in 5 patients were classified as pathogenic or probably pathogenic; three were novel variants containing candidate genes associated with ovarian development [19q13.43 (NLRP5) and Xq13.2 (XIST)] or function [(2q37.3 (PER2)]. The other pathogenic CNVs were previously implicated in POI etiology; two of them [Xq27.2q28 del (14.5 Mb) and Xq22.1q27.1 dup (41.4 Mb)] were encompassed in a complex chromosome rearrangement, associated with 20p13 dup (2.7 Mb), and the last region was 15q25.2 deletion. Four VUS containing genes associated with ovarian development [2p23.1 (XDH and EHD3), 9p24.1 (KDM4C), 22q12.1 (ZNRF3)] or function [1p31.1 (PTGFR)] were identified. CONCLUSION: CNVs analysis indicated a genetic etiology in 10% of these POI patients. New candidate genes associated with ovarian development and function were revealed. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:54 p.m. - 12:59 p.m.