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Measuring X-Chromosome inactivation skew for X-linked diseases with adaptive nanopore sequencing.

Authors :
Gocuk SA
Lancaster J
Su S
Jolly JK
Edwards TL
Hickey DG
Ritchie ME
Blewitt ME
Ayton LN
Gouil Q
Source :
Genome research [Genome Res] 2024 Nov 20; Vol. 34 (11), pp. 1954-1965. Date of Electronic Publication: 2024 Nov 20.
Publication Year :
2024

Abstract

X-linked genetic disorders typically affect females less severely than males owing to the presence of a second X Chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X-Chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, and its directionality and is applicable to all patients and X-linked variants. Enrichment of X Chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR -associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva, and buccal mucosa) and correlate it to phenotypic outcomes. This reveals a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritize patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic data sets, providing insights into disease risk and severity and aiding in the development of individualized strategies for X-linked variant carrier females.<br /> (© 2024 Gocuk et al.; Published by Cold Spring Harbor Laboratory Press.)

Details

Language :
English
ISSN :
1549-5469
Volume :
34
Issue :
11
Database :
MEDLINE
Journal :
Genome research
Publication Type :
Academic Journal
Accession number :
39284686
Full Text :
https://doi.org/10.1101/gr.279396.124