Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding...

Area of Science:

• Genetics
• Pediatric Medicine
• Molecular Biology

Background:

• Hirschsprung disease pathogenesis is complex, with the RET proto-oncogene frequently implicated.
• Rare coding sequence variants in RET explain a small fraction of Hirschsprung disease cases.

Purpose of the Study:

• To investigate the genetic underpinnings of Hirschsprung disease by combining genome-wide association analysis with RET exon sequencing.
• To identify genetic variants contributing to Hirschsprung disease in both familial and sporadic cases.

Main Methods:

• Genome-wide association study (GWAS) in 105 Hirschsprung disease cases and 386 controls.
• Sequencing of all RET exons to identify rare variants.
• Replication of previously identified associations in SEMA and NRG1 genes.

Main Results:

• A strong association between common non-coding RET variants and Hirschsprung disease was observed, particularly under a recessive genetic model (rs2435357, P = 1.462 × 10⁻²¹).
• Previously reported associations for SEMA and NRG1 variants were replicated.
• Twelve rare exonic RET variants were identified, with a minority of cases carrying these variants; however, these variants, in combination with common non-coding RET variants, contribute to the majority of cases.

Conclusions:

• Common non-coding RET variants, acting recessively, are a major genetic factor in Hirschsprung disease, explaining a significant proportion of sporadic cases.
• While rare RET variants are found in a subset of patients, their combined effect with common non-coding variants is crucial for disease etiology.
• The study highlights the importance of both common and rare genetic variations in the complex pathogenesis of Hirschsprung disease.