2ND LOCUS FOR HIRSCHSPRUNG-DISEASE WAARDENBURG-SYNDROME IN A LARGE MENNONITE KINDRED

We have studied a large Mennonite kindred in which 20 members were aff ected with Hirschsprung disease (HSCR), 5 of whom had one or more mani festations of Waardenburg; syndrome (WS) type II (WS2). Eleven additio nal relatives had signs of WS2 without HSCR. Since HSCR and WS2 each r epresent perturbations of neural crest migration/differentiation, this large pedigree with apparent cosegregation of HSCR and WS2 offered an opportunity to search for linkage between these loci, candidate genes , and random DNA markers, particularly in view of recent discoveries o f genes for Waardenburg syndrome type I (WS1) and Hirschsprung disease (c-ret). We have examined the following possible linked markers in 69 relatives in this family: the c-ret gene (HSCR); the human PAX3 gene (HuP2) on chromosome 2q (WS1) and placental alkaline phosphatase (ALPP ) on chromosome 2q (linked to WS1); argininosuccinate synthetase (ASS) on chromosome 9q, close to ABO blood groups which have shown weak lin kage to WS; and the beta 1 GABA receptor gene (GABARB1) on chromosome 4q13-11, close to c-kit, deletions of which cause piebaldism. Linkage between any of these loci and HSCR/WS in this kindred was excluded, de monstrating that there is at least one further locus for HSCR other th an c-ret. (C) 1994 Wiley-Liss, Inc.