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Sonic Hedgehog Intron Variant associated with an unusual Pediatric Cortical Cataract


Young, TL and Whisenhunt, KN and LaMartina, SM and Hewitt, AW and Mackey, DA and Hewitt, A, Sonic Hedgehog Intron Variant associated with an unusual Pediatric Cortical Cataract, Investigative Ophthalmology and Visual Science, 63, (6) Article 25. ISSN 1552-5783 (2022) [Refereed Article]

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DOI: doi:10.1167/iovs.63.6.25


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.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genomics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
UTAS Author:Mackey, DA (Professor David Mackey)
ID Code:155597
Year Published:2022
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-03-01
Last Modified:2023-03-01

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