Fabry Disease: Thirty-Five Mutations

Background: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the a-galactosidase A (a-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the a-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. Materials and Methods: Genomic DNA was isolated from affected probands and their family members. The seven a-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. Results: Two patients with the mild cardiac phenotype had niissense mutations, 191T and FI13L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R1OOT, Y134S, G138R, A143T, S148R, G163V, D17OV, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T -> C), and eight small exonic insertions or deletions (304dell, 613del9, 777dell, 1057de12, 1074del2, 1077dell, 1212del3, and 1094insl), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L12OX, respectively. Conclusions: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these famflies, and facilitate the identification of candidates for enzyme replacement therapy.