Abstract
BackgroundLeber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease.MethodsWe have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology.ResultsWe present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort.ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.
Highlights
The clinical hallmark of Leber congenital amaurosis (LCA) is the onset of severe visual impairment at or soon after birth
We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Summary
Between 1 June 2001 and 31 December 2015, 50 individuals with a clinical diagnosis of LCA from 40 unrelated pedigrees were enrolled into the AIRDR from ophthalmologist referrals or directly through expressions of interest received from individuals. An additional two siblings, affected at birth, from a consanguineous pedigree diagnosed with conerod dystrophy or fundus albipunctatus returned a molecular diagnosis consistent with LCA and were added to the cohort and referred for clinical re-evaluation. The 16 variants detected included seven nonsense, six frameshifting, and three splice site-related, and six were novel (Table 1/Table S1). This category was characterized by variants in five genes. Of seven variants detected in five pedigrees (19.2%; 5/26), two were novel, five were predicted to invoke NMD, and two occurred at splice sites. All individuals possessed one or two NMD variants, with CEP290:c.2991+1655G>A identified in 4/5 pedigrees This hypomorphic variant, well-established as pathogenic for LCA, causes insertion of a cryptic exon and subsequent truncation (den Hollander et al 2006).
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