Abstract
Background: Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the gastrointestinal tract, which consequences in intestinal obstruction. HSCR has more than 80% heritability, including two major forms as sporadically which is the most common form with a complex pattern of inheritance and other forms appear with a familial/syndromic basis along with Mendelian inheritance and incomplete penetrance. The rare and common sequence variants in genes related to the enteric nervous system (ENS) was identified to play a critical role in the progress of HSCR. Results: This study aimed to investigate the genetic basis of an Iranian extended family with different manifestations such as inherited HSCR, chronic constipation, congenital malformations (single kidney and closed anus) to find the causal mutations. To uncover the contributing genetic variant/s, exome sequencing was performed on proband (IV-V). Finally, with the standard filtering protocol, we identified a novel heterozygous nonsense mutation, p.Y314X at exon 5 of the RET gene. This variant is located in the extracellular domain of RET tyrosine kinase and subsequently leads to no detectable RET full-length protein and so may lead to protein loss of function. This devastating variant is manifested in the proband, with long‐segment form and other phenotypes such as single kidney, absent of peritoneum and pigmentation of the face. However, this variant has been segregated in the mother (III-IV, with single kidney), the grandmother (II-II, with diarrhea) and the aunt (III-V, with chronic constipation and premature ovarian failure); these members of the family didn’t show HSCR. Furthermore, in other members of the family (II-IV and III-XII) with chronic constipation and no HSCR, the variant was detected. Nonetheless, this phenomenon can be interpreted by incomplete or reduced penetrance in this extended family with variable expression. Conclusions: The present study found a novel null variant at RET gene that is associated with a wide range of phenotypes and incomplete penetrance. This can be synergistic effects of rare and/or common variants among known and/or unknown disease susceptibility genes which lead to variable severity of phenotype. Such information is important for proper genetic counseling in familial HSCR. Keywords : Hirschsprung disease, whole-exome sequencing, RET novel mutation, extended pedigree, incomplete penetrance.
Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease
