ESPEYB21 6. Differences of Sexual Development (DSD) and Gender Incongruence (GI) Clinical and Molecular Insights into SF1 Deficiency (3 abstracts)
6.7. Long-read genome sequencing reveals a novel intronic retroelement insertion in NR5A1 associated with 46,XY differences of sexual development
Del Gobbo GF , Wang X , Couse M , Mackay L , Goldsmith C , Marshall AE , Liang Y , Lambert C , Zhang S , Dhillon H , Fanslow C , Rowell WJ , Care4Rare Canada Consortium , Marshall CR , Kernohan KD & Boycott KM
Am J Med Genet A. 2024 May;194(5):e63522. doi: 10.1002/ajmg.a.63522. PMID: 38131126
Brief Summary: This study performed long-read genome sequencing (lr-GS) using PacBio HiFi on several members of a four-generation family presenting with autosomal dominant (AD) 46,XY differences of sexual development (DSD). This family had undergone a lengthy molecular diagnostic process with no conclusive results. Lr-GS offers enhanced mapping capabilities in highly repetitive, homologous, and low-complexity regions, providing better assessment of structural variations and complex genomic rearrangements compared to short-read genome sequencing (sr-GS).
The advent of sr-GS has significantly improved the detection of rare genetic disorders by extending sequencing beyond the exome, identifying non-coding and structural variations. While it is challenging to quantify the diagnostic yield improvement over exome sequencing, it may be as high as 10%. Lr-GS, which produces reads that are 100–1000 times longer, addresses many of sr-GS’s limitations, offering a more comprehensive genomic view (1, 2).
In this reported family, some individuals exhibited incomplete penetrance, with at least one unaffected 46,XY carrier. Affected members displayed various genital phenotypes, including hypospadias, ambiguous genitalia, dysgenetic testes, and reduced fertility. DNA from 4 affected participants across 2 generations was sequenced using the Sequel IIe system (PacBio), generating HiFi long reads. Lr-GS identified a novel SINE-VNTR-Alu (SVA) element insertion in intron 4 of NR5A1, linked to haploinsufficiency, a known mechanism in AD 46,XY DSD. This was missed b y sr-GS although it was called by 1 of the 3 structural variant tools in 3 of 5 affected individuals, due to the filtering criteria. Functional studies using RT-qPCR and RNA-Seq confirmed that the SVA insertion is associated with reduced NR5A1 expression, although differential expression could not be conclusively confirmed due to the lack of appropriate samples from controls.
This study highlights that retroelement insertions are likely an underestimated cause of unexplained rare genetic disorders. The utility of lr-GS as a promising tool for studying unexplained rare diseases is demonstrated, emphasizing the role of undiscovered non-coding variations in Mendelian disorders.
References: 1. Chaisson MJP, Sanders AD, Zhao X, et al. Multiplatform discovery of haplotype-resolved structural variations in human genomes. Nat Commun. 2019;10(1):1784. Published 2019 Apr 16. doi: 10.1038/s41467-018-08148-z2. Logsdon GA, Vollger MR, Eichler EE. Long-read Human Genome Sequencing and Applications. Nat Rev Genet. 2020;21(10):597-614. doi: 10.1038/s41576-020-0236-x
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
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