The genetic profile of Leber congenital amaurosis in an Australian cohort

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.

Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing

“…those for which potentially pathogenic variant(s) were not detected using the TS approach) were analysed via additional mutation screening (as described in the Methods section). None of the patients in these families carried the c.2991 + 1655A > G intronic variant in CEP290 that is frequently identified in European, Australian, and Brazilian families with LCA 5 , 7 , 8 . Neither were any of the analysed patients shown to harbour rare variants in five recently discovered LCA-associated genes ( CCT2 , CLUAP1 , DTHD1 , GDF6 , and IFT140 ) 20 – 24 , nor in exon 15 of RPGR , which is an alternative exon called ORF15 that contains highly repetitive purine-rich sequences (Supp.…”

“…recently reported two unrelated patients from Korean families with LCA that were compound heterozygous for the two variants 31 . They have since been detected in Japanese families, as well as those of various other ethnicities 6 – 8 , 12 , 13 , 17 , 31 . Conversely, nonsense, frameshift, or canonical splice-site variants in RPGRIP1 were identified in the three of the analysed families (EYE20, EYE55, and EYE149), as was the heterozygous RPGRIP1 exon-17 deletion (see families EYE16, EYE55, and JIKEI-122) (Table 2 ).…”

“…A total of 25 LCA-associated genes have been identified to date ( https://sph.uth.edu/retnet/ ; accessed 14th December 2017). Variants in these genes are estimated to cause approximately 70% of all LCA cases 5 – 8 .…”

Expanding the phenotypic spectrum in RDH12-associated retinal disease

“…Of (Coppieters et al 2010;Mackay et al 2011;Lee et al 2015;Thompson et al 2017;Jespersgaard et al 2019). The variant in this study, c.697G > A (p. Val233Ile), has been designated as causal in combination with c.619A > G (p.Asn207Asp) in a subject with macular dystrophy (OGI3076-4666), further adding to the heterogeneity in this region.…”

Edge of Scotoma Sensitivity as a Microperimetry Clinical Trial End Point in USH2A Retinopathy

“…Sequences were aligned to the USH2A reference sequence NM_206933.2, with nucleotide 1 corresponding to the A of the start codon ATG, and described in accordance with Human Genome Variation Society recommendations version 15.11. 28 Variant pathogenicity was assessed as previously described 29 and interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology joint guidelines. 30 …”