CONGENITAL CENTRAL HYPOVENTILATION SYNDROME - MUTATION ANALYSIS OF THE RECEPTOR TYROSINE KINASE RET

Congenital central hypoventilation syndrome (CCHS) usually occurs as a n isolated phenotype. However, 16% of the index cases are also affecte d with Hirschsprung disease (HSCR). Complex segregation analysis sugge sts that CCHS is familial and has the same inheritance pattern with or without HSCR We postulate that alteration of normal function of the r eceptor tyrosine kinase, RET, may contribute to CCHS based on RET's ex pression pattern and the identification of RET mutations in HSCR patie nts. To further explore the nature of the inheritance of CCHS, we have undertaken two main routes of investigation: cytogenetic analysis and mutation detection. Cytogenetic analysis of metaphase chromosomes sho wed normal karyotypes in 13 of the 14 evaluated index cases; one index case carried a familial pericentric inversion on chromosome 2. Mutati on analysis showed no sequence changes unique to index cases, as compa red to control individuals, and as studied by single strand conformati onal polymorphism (SSCP) analysis of the coding region of RET. We conc lude that point mutations in the RET coding region cannot account for a substantial fraction of CCHS in this patient population, and that ot her candidate genes involved in neural crest cell differentiation and development must be considered.