In:
Journal of Medical Genetics, BMJ
Abstract:
Genome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses ‘beyond the exome’ in regular care of patients with inherited retinal degeneration (IRD) or inherited optic neuropathy (ION). Methods PCR-free short-read GS was performed on 1000 consecutive probands with IRD/ION in routine diagnostics. Complementary whole-blood RNA-sequencing (RNA-seq) was done in a subset of 74 patients. An open-source bioinformatics analysis pipeline was optimised for structural variant (SV) calling and combined RNA/DNA variation interpretation. Results A definite genetic diagnosis was established in 57.4% of cases. For another 16.7%, variants of uncertain significance were identified in known IRD/ION genes, while the underlying genetic cause remained unresolved in 25.9%. SVs or alterations in non-coding genomic regions made up for 12.7% of the observed variants. The RNA-seq studies supported the classification of two unclear variants. Conclusion GS is feasible in clinical practice and reliably identifies causal variants in a substantial proportion of individuals. GS extends the diagnostic yield to rare non-coding variants and enables precise determination of SVs. The added diagnostic value of RNA-seq is limited by low expression levels of the major IRD disease genes in blood.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmg-2023-109470
Language:
English
Publisher:
BMJ
Publication Date:
2023
detail.hit.zdb_id:
2009590-9
SSG:
12
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