Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes.

Autor:	Molloy B; Genuity Science, Dublin, Ireland., Jones ER; Genuity Science, Dublin, Ireland., Linhares ND; Genuity Science, Dublin, Ireland., Buckley PG; Genuity Science, Dublin, Ireland., Leahy TR; Department of Paediatric Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland.; Department of Paediatrics, Trinity College, University of Dublin, Dublin, Ireland., Lynch B; Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland., Knerr I; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.; National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street, Dublin, Ireland., King MD; Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland., Gorman KM; Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2022 Sep 14; Vol. 13, pp. 945296. Date of Electronic Publication: 2022 Sep 14 (Print Publication: 2022).
DOI:	10.3389/fgene.2022.945296
Abstrakt:	A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1 , and a p (Pro222Leu) variant in PRKRA , respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis. Competing Interests: Authors BM, EJ, NL, and PB were employed by the company Genuity Science. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Molloy, Jones, Linhares, Buckley, Leahy, Lynch, Knerr, King and Gorman.)
Databáze:	MEDLINE
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