Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome

Idiopathic congenital central hypoventilation syndrome (CCHS) is a very rar e syndrome with major respiratory complications. Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunct ion (ANSD), we applied a case-control family study design to investigate th e genetics of ANSD, Fifty-two probands with CCHS were identified, as well a s 52 age-, race-, and gender-matched controls. ANSD phenotypic features wer e characterized in the cases, controls, and their family members. Our earli er studies found that most ANSD symptoms were more likely in CCHS cases and their relatives than in controls and their relatives (P < 0.05). The goal of the current study was to determine if the familiality of ANSD was consis tent with a genetic pattern. We performed major locus segregation analysis of ANSD utilizing regressive models. CCHS probands were assumed to be affec ted; controls and relatives were designated as affected if they had two or more relevant symptoms. The hypothesis of "no transmission and no familial effects" was rejected in both case and control families. Case families were consistent with transmission of a major effect; control families were not (the difference in the pattern of results was significant, P < 0.0001). In the total data set, the best-fitting model was codominant Mendelian inherit ance of a major gene for ANSD. These case-control family studies support ou r hypothesis that CCHS is the most severe manifestation of a general ANSD, with a family pattern consistent with Mendelian transmission, and demonstra te the potential utility of the approach to studies of other, similarly int ractable disorders, (C) 2001 Wiley-Liss, Inc.