Segregation analysis in Shwachman-Diamond syndrome: Evidence for recessiveinheritance

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports hav e indicated the occurrence of affected siblings, but formal segregation ana lysis has not been performed. In families collected for genetic studies, th e mean paternal age and mean difference in parental ages were found to be c onsistent with the general population. We determined estimates of segregati on proportion in a cohort of 84 patients with complete sibship data under t he assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All thr ee estimates supported an autosomal recessive mode of inheritance, but comp lete ascertainment was found to be unlikely. Although there are no overt si gns of disease in adult carriers (parents), the use of serum trypsinogen le vels to indicate exocrine pancreatic dysfunction was evaluated as a potenti al measure for heterozygote expression. No consistent differences were foun d in levels between parents and a normal control population. Although genet ic heterogeneity cannot be excluded, our results indicate that simulation a nd genetic analyses of Shwachman-Diamond syndrome should consider a recessi ve model of inheritance.