ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 6.9 | DOI: 10.1530/ey.19.6.9


Mol Cell Endocrinol. 2022 Apr 15;546:111570. PMID: 35051551, doi: 10.1016/j.mce.2022.111570.

Brief Summary: This report emphasizes the importance of screening for copy number variants (CNVs) using parallel genomic techniques for diagnosing unsolved cases of complete androgen insensitivity syndrome (CAIS) as well as other DSDs, where traditional sequencing techniques fail to detect a genetic cause.

The authors used a specific bioinformatics protocol (Ximmer pipeline) developed by Sadedin et al. (1) to detect CNVs using whole-exome sequencing (WES) data. They identified one 46,XY female patient with CAIS due to a rare duplication of exon 2 of the androgen receptor (AR) gene, and two siblings with primary ovarian failure (POI) due to homozygous deletion in FSHR and another POI patient with a heterozygous deletion in NR5A1. A specific molecular etiology was not identified in these 3 patients by targeted gene sequencing panel and whole-exome sequencing (WES) at initial investigations.

Androgen insensitivity syndrome (AIS) is a rare DSD resulting from variants of the X-linked AR. Patients with CAIS have a 46,XY karyotype and present with normal female external genitalia, bilateral intra-abdominal or inguinal testes, the absence of Müllerian structures, hypoplastic or absent Wolffian structures, primary amenorrhea, normal breast development, absent or sparse pubic hair. The prevalence of genetically confirmed CAIS ranges from 1:20400 to 1:99,100 46,XY individuals. Sanger sequencing or multi-gene massively parallel sequencing panels confirm the diagnosis of over 95% of CAIS patients. For cases where no variant is detected in AR, other technologies such as WES and array comparative genomic hybridization (CGH) may be used, with the former technique typically detecting single nucleotide variations (SNVs) and small insertions/deletions (INDELs) and the latter identifying copy number variations (CNVs). While whole-genome sequencing (WGS) may also be used to detect CNVs, it is currently not feasible for high throughput clinical diagnostics due to high costs.

Instead of targeted gene panel tests conducted concurrently with array CGH analysis for genetic diagnosis to detect SNVs, INDELs as well as CNVs, this study shows the utility of Ximmer bioinformatics pipeline by analyzing WES data as a single test, sufficient for this purpose. The use of this technique would save cost and time for both the patient and clinician. Furthermore, genomic testing offers a less invasive approach and could be routinely used for genetic diagnosis of CAIS patients in place of techniques that rely on the isolation of genital skin fibroblasts from the patient.

References: 1 Sadedin SP, Ellis JA, Masters SL, Oshlack A. Ximmer: a system for improving accuracy and consistency of CNV calling from exome data. Gigascience. 2018 Oct 1;7(10):giy112. doi: 10.1093/gigascience/giy112. PMID: 30192941; PMCID: PMC6177737.

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