Novel splicing missense and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease

We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (A1019-1020), three mis-sense (Argl56> His, ArglOl> Leu, Val177> Met), and three splicing defects (IVS 5, 5'ss T "> A; IVS 10, 5'ss G"'> A; IVS 10, 3'ss G-3 '> A). Four of the mutations generated stop signals at codons 131, 321, 334, and 348; transcripts of all but the last, due to A1019-1020, were severely reduced. A1019-1020 (like A955-959, found in one patient and appar-ently recurrent) is at a short deletional hot spot. Arg156> His, the product of which had detectable activity, was found in thre