Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.
Mov Disord
; 39(3): 486-497, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38197134
ABSTRACT
BACKGROUND:
Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive.OBJECTIVES:
Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region.METHODS:
We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features.RESULTS:
Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare.CONCLUSIONS:
These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia Cerebelar
/
Ataxias Espinocerebelares
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Mov Disord
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Reino Unido