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

Author(s)

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

• Document type: Journal article
• Source: JOURNAL OF THE ENDOCRINE SOCIETY; v. 6, n. 9, p. 10-pg., 2022-09-01.

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. (AU)

• FAPESP's process: 15/17350-0 - Molecular analysis of Candidates Genes for Polycystic Ovary Syndrome Through New Generation Sequencing
• Grantee: Larissa Garcia Gomes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/27631-7 - Genetic and epigenetic studies of endocrine disorders related with reproductive axis
• Grantee: Ana Claudia Latronico Xavier
• Support Opportunities: Research Projects - Thematic Grants