Cystathionine β‐synthase deficiency in Georgia (USA): Correlation of clinical and biochemical phenotype with genotype

Cystathionine beta‐synthase (CBS) deficiency is a rare autosomal recessive disorder that is the most frequent cause of clinical homocystinuria. Patients not treated in infancy have multi‐systems disorders including dislocated lenses, mental deficiency, osteoporosis, premature arteriosclerosis, and thrombosis. In this paper, we examine the relationship of the clinical and biochemical phenotypes with the genotypes of 12 CBS deficient patients from 11 families from the state of Georgia, USA. By DNA sequencing of all of the coding exons we identified mutations in the CBS genes in 21 of the 22 possible mutant alleles. Ten different missense mutations were identified and one novel splice‐site mutation was found. Five of the missense mutations were previously described (G307S, I278T, V320A, T353M, and L101P), while five were novel (A226T, N228S, A231L, D376N, Q526K). Each missense mutation was tested for function by expression in S. cerevisiae and all were found to cause decreased growth rate and to have significantly decreased levels of CBS enzyme activity. The I278T and T353M mutations accounted for 45% of the mutant alleles in this patient cohort. The T353M mutation, found exclusively in four African American patients, was associated with a B6‐nonresponsive phenotype and detection by newborn screening for hypermethioninemia. The I278T mutation was found exclusively in Caucasian patients and was associated with a B6‐responsive phenotype. We conclude that these two mutations occurred after ethnic socialization and that the CBS genotype is predictive of phenotype. Hum Mutat 22:434–441, 2003. © 2003 Wiley‐Liss, Inc.