Genetic mosaicism of a frameshift mutation in the RET gene in a family with Hirschsprung disease.

[hirschsprung disease]

Mutations and polymorphisms in the RET gene are a major cause of Hirschsprung disease (HSCR ). Theoretically , all true heterozygous patients with a new manifestation of a genetically determined disease must have parents with a genetic mosaicism of some extent . However , no genetic mosaicism has been described for the RET gene in HSCR yet . Therefore , we analyzed families with mutations in the RET gene for genetic mosaicism in the parents of the patients . Blood samples were taken from patients with HSCR and their families /parents to sequence the RET coding region . Among 125 families with HSCR , 33 families with RET mutations were analyzed . In one family , we detected a frameshift mutation due to a loss of one in a row of four cytosines in codon 117 /118 of the RET gene (c .352 delC ) leading to a frameshift mutation in the protein (p .Leu 118 Cysfs *105 ) that affected two siblings . In the blood sample of the asymptomatic father we found a genetic mosaicism of this mutation which was confirmed in two independent samples of saliva and hair roots . Quantification of peak-heights and comparison with different mixtures of normal and mutated plasmid DNA suggested that the mutation occurred in the early morula stadium of the founder , between the 4 - and 8 -cell stages . We conclude that the presence of a RET mutation leading to loss of one functional allele in 20 to 25 % of the cells is not sufficient to cause HSCR . The possibility of a mosaicism has to be kept in mind during genetic counseling for inherited diseases .