Genetics of Hirschsprung's disease

Area of Science:

• Genetics
• Developmental Biology
• Gastroenterology

Background:

• Hirschsprung's disease (HSCR) is a congenital bowel obstruction caused by the absence of enteric ganglia.
• It serves as a key model for studying enteric neuropathies.
• HSCR affects approximately 2-2.8 in 10,000 newborns.

Purpose of the Study:

• To review the current genetic landscape of Hirschsprung's disease.
• To discuss the interplay of common and rare genetic variants in HSCR.
• To explore challenges and propose solutions for clinical translation of genetic findings.

Main Methods:

• Review of recent genome-wide association studies (GWAS) and next-generation sequencing (NGS) findings.
• Analysis of genetic heterogeneity, penetrance, expressivity, and gene-gene interactions in HSCR.
• Discussion of clinical translation obstacles and potential advancements.

Main Results:

• Numerous HSCR candidate genes have been identified through GWAS and NGS.
• Genetic heterogeneity, variable penetrance, and complex interactions characterize HSCR genetics.
• Common and rare variants likely modulate HSCR's phenotypic presentation.

Conclusions:

• Advances in genetic studies offer new insights into HSCR's molecular mechanisms.
• Translating genetic discoveries into risk prediction and optimized clinical outcomes remains a significant challenge.
• Addressing these challenges is crucial for advancing precision medicine and developing novel therapies for HSCR.