Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion.

Autor: Poleg T; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Proskorovski-Ohayon R; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Dolgin V; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Hadar N; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Safran A; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Agam N; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Jean MM; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Freund O; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Gradstein L; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Shelef I; Department of Radiology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel., Sadaka Y; Child Development Center, Ministry of Health, and Azrieli National Centre for Autism, Ben-Gurion University, Beer-Sheva, Israel., Birk OS; Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.; Genetics Institute, Soroka Medical Center, Beer-Sheva, Israel.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2024 Nov 25. Date of Electronic Publication: 2024 Nov 25.
DOI: 10.1111/cge.14653
Abstrakt: Biallelic mutations in BRAT1 result in lethal neonatal rigidity and multifocal seizure syndrome and a milder neurodevelopmental disorder of cerebellar atrophy with or without seizures (NEDCAS, MIM 618056). Combining linkage analysis and whole-genome sequencing (WGS), we identified a novel deep intronic BRAT1 variant, NC_000007.14 (NM_152743.4):c.128-1585 T > G, in 3 siblings of a consanguineous Bedouin family exhibiting NEDCAS. In silico analyses followed by molecular studies demonstrated this variant's impact on splice regulatory elements, forming a cryptic exon, resulting in a deleterious frameshift and aberrant transcript. Previously reported pathogenic BRAT1 splice-site mutations were adjacent to exons, affecting canonical consensus splice sites, and identifiable by whole-exome sequencing. The deep intronic BRAT1 disease-causing variant is thus unique and underscores the potential of intronic splice regulatory elements in BRAT1 disease pathogenesis, demonstrating the utility of WGS in identifying noncoding variants in unresolved cases. The affected individuals (deep into their twenties) are among the longest-surviving patients described to date-delineating the NEDCAS phenotype at these ages. Although sharing homozygosity of the same variant, they show varying penetrance of nystagmus and extreme variability in the extent of ataxia and age of onset of developmental delay. Notably, we summarize all documented BRAT1 splice variants reported to date and their phenotypic associations.
(© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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