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Stuart W. Tompson, Kristina N. Whisenhunt, Alex W Hewitt, David A Mackey, Terri L Young; Intronic variant in sonic hedgehog associated with autosomal dominant pediatric cataract, myopic astigmatism, familial exudative vitreoretinopathy, and primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):5.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the genetic etiology of an autosomal dominant constellation of pediatric cortical cataract, asymmetric myopia with astigmatism, familial exudative vitreoretinopathy, and primary open-angle glaucoma phenotypes in a large Australian pedigree of European decent we performed linkage analysis, as well as exome and whole-genome sequencing (WGS).
Twelve affected and 4 unaffected individuals were genotyped at 713K SNPs using HumanOmniExpress-24 BeadChips, and 103K high quality and informative markers were selected via GenomeStudio software. Multipoint linkage analysis and haplotyping were performed by Superlink-Online software (dominant inheritance, 0.99 penetrance). Four affected individuals were exome sequenced using a Roche Nimblegen SeqCap EZ Exome V3 capture kit and an Illumina HiSeq2000 platform (2x100bp, 100x coverage). WGS was performed on an affected individual and his unaffected father using an Illumina HiSeq X Ten platform (2x150bp, 30x coverage). Reads were aligned to hg19 with BWA. SNPs/InDels, structural variants, and copy number variants (CNVs) were called with GATK, Delly, and control-FREEC, respectively. Variant analysis was performed using Golden Helix SVS. Combined Annotation Dependent Depletion (CADD) analysis prioritized variants by predicted deleteriousness.
Linkage mapped the genetic locus to chromosome 7q36 (LOD 3.3). A co-segregating disease haplotype delimited the interval containing 27 protein coding and 17 non-protein coding genes. No candidate coding variants were identified. WGS discovered 136 rare (allele frequency <0.0001) non-coding variants, of which 77 were associated with 13 genes. CADD analysis determined only 1 variant within the top 1% of deleterious variants in the genome (scaled score 21.7) - a novel base substitution located in a highly conserved CpG island between exons 1 and 2 of sonic hedgehog (SHH; NM_001310462.2: c.300+290C>T). Extensive published animal studies link SHH to the phenotypes of this family. ENCODE data suggested that the region may act as a distal enhancer during early development of human eye and retinal tissues.
We identified an intronic variant in SHH as a potential cause of this rare constellation of ocular phenotypes. Disruption of the cis-regulatory enhancer element in SHH may lead to abnormal ocular development.
This is a 2021 ARVO Annual Meeting abstract.
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