Sonic Hedgehog Intron Variant Associated With an Unusual Pediatric Cortical Cataract.
Invest Ophthalmol Vis Sci
; 63(6): 25, 2022 06 01.
Article
em En
| MEDLINE
| ID: mdl-35749127
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catarata
/
Proteínas Hedgehog
Tipo de estudo:
Risk_factors_studies
Limite:
Child
/
Humans
País/Região como assunto:
Oceania
Idioma:
En
Revista:
Invest Ophthalmol Vis Sci
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos