Журнал гепатологии и желудочно-кишечных расстройств
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Assessment and Documentation of Indigenous and a Novel Nonsense RET Variant in an Extended Hirschsprung Iranian Pedigree with Reduced Penetrance and Variable Expression

Sahereh Rahnavard, Maryam Eghbali, Hassan Saei, Roya Ghaffarnia, Amin Ardeshirdavani, Bahar Ashjaei, Maryam Abir

Objective(s): Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the gastrointestinal tract, resulting in intestinal obstruction. HSCR has two significant forms: sporadic and familial/syndromic. This study aimed to investigate the genetic basis of HSCR in an Iranian extended family to explore the causal mutations.

Materials and Methods: DNA extraction was carried out from blood specimens of the twelve affected and unaffected family members. Then, Whole Exome Sequencing (WES) was performed for patients IV-V, and the identified variant was validated by Sanger sequencing in the proband IV-V. Finally, a segregation analysis was conducted on the parents and other affected and unaffected family members.

Results: We have identified a novel heterozygous nonsense mutation with the standard filtering protocol, p.Y314X, at exon 5 of the RET gene. This devastating variant was manifested in the proband with long-segment form and other phenotypes such as single kidney, absence of peritoneum, and the face’s pigmentation. However, this variant has been segregated into the mother, the grandmother, and the aunt. These members of the family did not show HSCR. Furthermore, this variant was detected in other family members (II-IV and III-XII) with chronic constipation and no HSCR.

Conclusion: The present study has found a novel nonsense variant at the RET gene associated with a wide range of phenotypes and incomplete penetrance. The synergistic effects of rare and common variants among known and unknown disease susceptibility genes lead to variable severity. Such information is vital for proper genetic counseling in familial HSCR.