Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology and Metabolism
Lidija K GorsicM Urbanek

Abstract

Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. To our knowledge, this study is the first to identif...Continue Reading

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Citations

Feb 16, 2019·Expert Review of Endocrinology & Metabolism·David H AbbottJon E Levine
Mar 8, 2019·The Journal of Clinical Endocrinology and Metabolism·Laura C TorchenAndrea Dunaif
May 1, 2019·The Journal of Clinical Endocrinology and Metabolism·Matthew DapasM Geoffrey Hayes
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Jul 8, 2019·Neuroendocrinology·Anne-Laure BarbotinPaolo Giacobini

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