RET somatic mutations are underrecognized in Hirschsprung disease.

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Surgery

Background:

• Hirschsprung disease (HSCR) is a congenital disorder affecting the enteric nervous system.
• The RET proto-oncogene is a major susceptibility gene for HSCR.
• Mosaic mutations, where a mutation is present in some cells but not others, can be challenging to detect.

Purpose of the Study:

• To determine the frequency of RET mosaicism in Hirschsprung disease (HSCR).
• To assess if RET mosaicism has been previously underestimated in HSCR.
• To evaluate the contribution of RET mosaicism to HSCR risk.

Main Methods:

• Targeted exome sequencing and RET single-gene screening were performed on 152 patients.
• Amplicon-based deep sequencing was used on multiple tissue samples (blood, colon, saliva).
• TA cloning and sequencing were employed for mutation validation.

Main Results:

• Eight de novo mutations were identified in 152 patients (5.2%), with six being pathogenic mosaic mutations.
• Somatic mosaicism was detected in two patients in blood, colon, and saliva (mutant allele frequency: 35-44%).
• Germline mosaicism was found in four unaffected individuals with affected children, across multiple tissues (mutant allele frequency: 1-28%).

Conclusions:

• Somatic RET gene mutations are underrecognized in Hirschsprung disease.
• Molecular investigation of parents is crucial for determining recurrence risk in families with seemingly sporadic HSCR mutations.