Mutations in JAGGED1 gene are predominantly sporadic in alagille syndrome

Backgrounds & Aims: Mutations in the JAGGED1 gene are responsible for the A lagille syndrome, an autosomal dominant disorder characterized by neonatal jaundice, intrahepatic cholestasis, and developmental disorders affecting t he liver, heart, vertebrae, eyes, and face. We screened a large group of pa tients for mutations in JAGGED1 and studied transmission of the mutations. Methods: The coding sequence of the JAGGED1 gene was searched by single-str and conformation polymorphism and sequence analysis for mutations in 109 un related patients with the Alagille syndrome and their family if available. Results: Sixty-nine patients (63%) had intragenic mutations, including 14 n onsense mutations, 31 frameshifts, 11 splice site mutations, and 13 missens e mutations. We identified 59 different types of mutation of which 54 were previously undescribed; 8 were observed more than once. Mutations were de n ovo in 40 of 57 probands. Conclusions: Most of the observed mutations other than the missense mutations in JAGGED1 are expected to give rise to trunca ted and unanchored proteins. All mutations mapped to the extracellular doma in of the protein, and there appeared to be regional hot spots, although no clustering was observed. Thus, the sequencing of 7 exons of JAGGED1 would detect 51% of the mutations, Transmission analysis showed a high frequency of sporadic cases (70%).