Analysis of intragenic USH2A copy number variation unveils broad spectrum of unique and recurrent variants.
Eur J Med Genet
; 61(10): 621-626, 2018 Oct.
Article
en En
| MEDLINE
| ID: mdl-29655801
ABSTRACT
Given that all forms of Usher syndrome (USH) present with hearing loss in advance of retinal disease, the syndromic nature of the disorder is rarely appreciated when critical management decisions are being made. As a result, molecular diagnostics are crucial in guiding the management of USH patients. While 11 genes have been associated with USH, the USH2A gene is one of the largest contributors. Approximately 20% of suspected USH probands that undergo USH2A sequencing at our laboratory receive an inconclusive result due to the identification of a monoallelic disease-causing variant in USH2A. Many studies suggest that intragenic deletions and duplications represent an important USH2A variant type that can be missed by sequencing assays if supplemental algorithms or testing methods are not applied. To gain a comprehensive view of the contribution of USH2A CNVs to USH, we conducted prospective and retrospective screening in 700 hearing loss probands. Fourteen individuals with 11 unique USH2A CNVs are reported, including one pathogenic multi-exon duplication. Additionally, we mapped deletion breakpoints and performed a meta-analysis of USH2A CNVs to evaluate recurrence and underlying mechanisms. This analysis revealed breakpoint grouping within three introns, raising the possibility of CNV-susceptible regions within the gene. Overall, our data highlight the diversity of pathogenic CNVs in this gene, demonstrating that the comprehensive, high-resolution USH2A CNV analysis methods employed here are essential components of clinical genetic testing for USH.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de la Matriz Extracelular
/
Síndromes de Usher
/
Variaciones en el Número de Copia de ADN
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2018
Tipo del documento:
Article