Sonic Hedgehog Intron Variant Associated With an Unusual Pediatric Cortical Cataract.

Area of Science:

• Genetics
• Ophthalmology
• Developmental Biology

Background:

• Pediatric cataracts are a leading cause of vision impairment in children.
• Genetic factors play a significant role in the etiology of congenital and pediatric cataracts.
• Understanding the genetic basis of rare cataract forms can elucidate lens development pathways.

Purpose of the Study:

• To identify the genetic cause of a unique pediatric cortical cataract.
• To investigate autosomal dominant inheritance in a large European-Australian family.
• To pinpoint the specific genetic variant responsible for the observed phenotype.

Main Methods:

• Whole exome and whole genome sequencing were performed on affected and unaffected individuals.
• Linkage analysis and haplotyping were used to narrow down the disease-associated region.
• Bioinformatic analyses, including Combined Annotation Dependent Depletion (CADD), identified candidate variants.
• Luciferase reporter assays were employed to functionalize the identified variant's effect on gene expression.

Main Results:

• Linkage mapping identified a critical region on chromosome 7q36.
• Whole-genome sequencing revealed a novel, highly deleterious noncoding variant in intron-1 of the sonic hedgehog (SHH) gene.
• This variant was predicted to affect an enhancer region crucial for SHH expression.
• Functional assays confirmed the variant's role in enhancing SHH activity in eye tissues.

Conclusions:

• A specific intronic variant in the SHH gene is associated with an unusual pediatric cortical cataract.
• SHH plays a critical role in lens development, and its dysregulation can lead to cataracts.
• The findings suggest that altered enhancer activity of SHH contributes to the pathogenesis of this specific cataract type.