High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort

Raiane P Crespo; Thais P Rocha; Luciana R Montenegro; Mirian Y Nishi; Alexander A L Jorge; Gustavo A R Maciel; Edmund Baracat; Ana Claudia Latronico; Berenice B Mendonca; Larissa G Gomes

doi:10.1210/jendso/bvac106

High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort

J Endocr Soc. 2022 Jul 5;6(9):bvac106. doi: 10.1210/jendso/bvac106. eCollection 2022 Sep 1.

Affiliations

¹ Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
² Unidade de Endocrinologia Genética (LIM 25), Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
³ Disciplina de Ginecologia, Faculdade de Medicina da Universidade de São Paulo, Brazil.

Abstract

Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component.

Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort.

Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing.

Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants).

Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.

Keywords: exome sequencing; genetics; insulin resistance; polycystic ovary syndrome; target sequencing.