Combined Hamartoma of the Retina and Retinal Pigment Epithelium in a Patient with Gorlin Syndrome: Spontaneous Partial Resolution of Traction Caused by Epiretinal Membrane

Purpose To identify the genetic basis of an unusual pediatric cortical cataract demonstrating autosomal dominant inheritance in a large European–Australian pedigree. Methods DNA from four affected individuals were exome sequenced utilizing a NimbleGen SeqCap EZ Exome V3 kit and HiSeq 2500. DNA from 12 affected and four unaffected individuals were genotyped using Human OmniExpress-24 BeadChips. Multipoint linkage and haplotyping were performed (Superlink-Online SNP). DNA from one affected individual and his unaffected father were whole-genome sequenced on a HiSeq X Ten system. Rare small insertions/deletions and single-nucleotide variants (SNVs) were identified in the disease-linked region (Golden Helix SVS). Combined Annotation Dependent Depletion (CADD) analysis predicted variant deleteriousness. Putative enhancer function and variant effects were determined using the Dual-Glo Luciferase Assay system. Results Linkage mapping identified a 6.23-centimorgan support interval at chromosome 7q36. A co-segregating haplotype refined the critical region to 6.03 Mbp containing 21 protein-coding genes. Whole-genome sequencing uncovered 114 noncoding variants from which CADD predicted one was highly deleterious, a novel substitution within intron-1 of the sonic hedgehog signaling molecule ( SHH ) gene. ENCODE data suggested this site was a putative enhancer, subsequently confirmed by luciferase reporter assays with variant-associated gene overexpression. Conclusions In a large pedigree, we have identified a SHH intron variant that co-segregates with an unusual pediatric cortical cataract phenotype. SHH is important for lens formation, and mutations in its receptor ( PTCH1 ) cause syndromic cataract. Our data implicate increased function of an enhancer important for SHH expression primarily within developing eye tissues.

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Combined Hamartoma of the Retina and Retinal Pigment Epithelium in a Patient with Gorlin Syndrome: Spontaneous Partial Resolution of Traction Caused by Epiretinal Membrane

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References 9 publications

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Photocoagulation-associated spontaneous release of epiretinal membrane secondary to retinal vascular tumor: case series of 8 cases

Sonic Hedgehog Intron Variant Associated With an Unusual Pediatric Cortical Cataract

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