A review of genetic mutation in familial Hirschsprung's disease in South Africa: towards genetic counseling.

BACKGROUND: Hirschsprung's disease (HSCR) represents a complex disorder of signaling molecules, resulting from the effects of at least 9 known susceptibility genes. Affected families carry 200 times higher risk, but genetic counseling via pedigree analysis is difficult and the significance of genetic variations is unclear. This study evaluated a set of patients affected by HSCR with familial recurrence to evaluate factors of greatest value in genetic counseling. PATIENTS AND METHODS: One hundred twenty patients with HSCR (including 18 kindreds) were screened for genetic variations of the 2 major susceptibility genes (RET and endothelin B receptor [EDNRB]) and compared with 60 control samples (20 per ethnic group). Familial recurrence patterns were studied for patient sex, pattern of recurrence, presence of associated syndromic features, and genetic features of major susceptibility genes. Polymerase chain reaction and HEX-SSCP analysis were performed on DBA extracted from blood/microdissected tissue samples. SSCP variants were validated and automated sequencing techniques performed on polymerase chain reaction products showing conformational variants in acrylamide gel.
RESULTS: Familial cases had a male-female ratio of 1.5:1, male-to-male transmission (n = 10; 2 father to son), female-to-male transmissions (n = 4; 3 female carriers, female-to-female (n = 4; 2 mother to daughter), and 1 paternal RET deletion-female with very long segment aganglionosis. Increasing gene penetrance occurred in 3 pedigrees. An increased incidence of long segment HSCR was noted in families with recurrence and appeared important. No consistent mendelian trends or specific genetic sites were observed, but 3 suggested autosomal dominant and recessive in a further 3. Identified genetic variations included deletions, frame shifts, and missense mutations, as well as a number of significant single nucleotide polymorphism variations. Transmitted RET mutations occurred in 5 (30%) of 16 kindreds. Splice RET mutation plus variants of exon 17 (973L) affected 2 children with identical total colonic aganglionosis. In a 3-generation family, variations in RET exons 6, 13, and 18 (928) affected 3 male children with increasing penetration to recur as total intestinal aganglionosis in a grandchild.
CONCLUSIONS: Mendelian transmission appears mediated by the RET proto-oncogene. EDNRB mutations suggest haplotypic gene-gene interaction. Genetic counseling remains a challenge in HSCR because of its multfactorial etiology.