Details

Autor(en) / Beteiligte

• Del Gobbo, Giulia F.
• Wang, Xueqi
• Couse, Madeline
• Mackay, Layla
• Goldsmith, Claire
• Marshall, Aren E.
• Liang, Yijing
• Lambert, Christine
• Zhang, Siyuan
• Dhillon, Harsharan
• Fanslow, Cairbre
• Rowell, William J.
• Marshall, Christian R.
• Kernohan, Kristin D.
• Boycott, Kym M.

Titel

Long‐read genome sequencing reveals a novel intronic retroelement insertion in NR5A1 associated with 46,XY differences of sexual development

Ist Teil von

• American journal of medical genetics. Part A, 2024-05, Vol.194 (5), p.e63522-n/a

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2024

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Despite significant advancements in rare genetic disease diagnostics, many patients with rare genetic disease remain without a molecular diagnosis. Novel tools and methods are needed to improve the detection of disease‐associated variants and understand the genetic basis of many rare diseases. Long‐read genome sequencing provides improved sequencing in highly repetitive, homologous, and low‐complexity regions, and improved assessment of structural variation and complex genomic rearrangements compared to short‐read genome sequencing. As such, it is a promising method to explore overlooked genetic variants in rare diseases with a high suspicion of a genetic basis. We therefore applied PacBio HiFi sequencing in a large multi‐generational family presenting with autosomal dominant 46,XY differences of sexual development (DSD), for whom extensive molecular testing over multiple decades had failed to identify a molecular diagnosis. This revealed a rare SINE‐VNTR‐Alu retroelement insertion in intron 4 of NR5A1, a gene in which loss‐of‐function variants are an established cause of 46,XY DSD. The insertion segregated among affected family members and was associated with loss‐of‐expression of alleles in cis, demonstrating a functional impact on NR5A1. This case highlights the power of long‐read genome sequencing to detect genomic variants that have previously been intractable to detection by standard short‐read genomic testing.