MUTATION CHARACTERIZATION AND GENOTYPE-PHENOTYPE CORRELATION IN BARTH-SYNDROME

Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-me thylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. We have now evaluated 14 Barth syndrome pedigrees for mutations in G4.5 and have identified unique mutations in all, including four splice-sit e mutations, three deletions, one insertion, five missense mutations, and one nonsense mutation. Nine of the 14 mutations are predicted to s ignificantly disrupt the protein products of G4.5. The occurrence of m issense mutations in exons 3 and 8 suggests that these exons encode es sential portions of the G4.5 proteins, whose functions remain unknown. We found no correlation between the location or type of mutation and any of the clinical or laboratory abnormalities of Barth syndrome, whi ch suggests that additional factors modify the expression of the Barth phenotype. The characterization of mutations of the G4.5 gene will be useful for carrier detection, genetic counseling, and the identificat ion of patients with Barth syndrome who do not manifest all of the car dinal features of this disorder.