Whole exome sequencing reveals copy number variants in individuals with disorders of sex development

Rajini Sreenivasan; Katrina Bell; Jocelyn van den Bergen; Gorjana Robevska; Daniele Belluoccio; Rachana Dahiya; Gary M Leong; Jérôme Dulon; Philippe Touraine; Elena J Tucker; Katie Ayers; Andrew Sinclair

doi:10.1016/j.mce.2022.111570

Whole exome sequencing reveals copy number variants in individuals with disorders of sex development

Mol Cell Endocrinol. 2022 Apr 15:546:111570. doi: 10.1016/j.mce.2022.111570. Epub 2022 Jan 18.

Affiliations

¹ Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
² Murdoch Children's Research Institute, Melbourne, Australia.
³ Agilent Technologies Pty. Ltd., Melbourne, Australia.
⁴ Queensland Children's Hospital, Brisbane, Australia; The University of Queensland, Brisbane, Australia.
⁵ Department of Paediatrics, Nepean Hospital and Charles Perkins Centre Nepean Research Hub, University of Sydney, NSW, Australia.
⁶ Department of Endocrinology and Reproductive Medicine, AP-HP, Sorbonne University Medicine, Centre de Référence desMaladies Endocriniennes Rares de la Croissance et du Développement, Centre des Pathologies Gynécologiques Rares, Paris, France.
⁷ Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: andrew.sinclair@mcri.edu.au.

PMID: 35051551
DOI: 10.1016/j.mce.2022.111570

Abstract

Complete androgen insensitivity syndrome (CAIS), where 46,XY individuals present as female, is caused by variants in the androgen receptor gene (AR). We analyzed the DNA of a patient with suspected CAIS using a targeted gene sequencing panel and whole exome sequencing (WES) but did not detect any small nucleotide variants in AR. Analysis of WES data using our bioinformatics pipeline designed to detect copy number variations (CNV) uncovered a rare duplication of exon 2 of AR. Using array comparative genomic hybridization, the duplication was found to span 43.6 kb and is predicted to cause a frameshift and loss of AR protein. We confirmed the power of our WES-CNV detection protocol by identifying pathogenic CNVs in FSHR and NR5A1 in previously undiagnosed patients with disorders of sex development. Our findings illustrate the usefulness of CNV analysis in WES data to detect pathogenic genomic changes that may go undetected using only standard analysis protocols.

Keywords: Androgen receptor; Complete androgen insensitivity syndrome; Copy number variation; Disorders of sex development; Exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen-Insensitivity Syndrome* / genetics
Comparative Genomic Hybridization
DNA Copy Number Variations* / genetics
Exome / genetics
Exome Sequencing / methods
Female
High-Throughput Nucleotide Sequencing / methods
Humans
Male