Fabry disease: Comparison of enzymatic, linkage, and mutation analysis forcarrier detection in a family with a novel mutation (30delG)

Fabry disease (FD) is an X-linked recessive disorder caused by the deficien t activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Aff ected males are reliably diagnosed by demonstration of deficient alpha-Gal A activity in plasma or leukocytes, However, identification of female carri ers is problematic due to Lyonization, requiring mutation identification an d/or linkage studies for accurate carrier detection. Here, we describe a la rge Brazilian kindred with Fabry disease that permitted comparison of bioch emical and molecular diagnostic techniques. Initially, the plasma alpha-Gal A activities were determined in at-risk affected males and potential femal e carriers; affected males were readily diagnosed, while the females had va riable results. To detect carrier females, haplotype analysis using 10 poly morphic markers adjacent to the gene was performed. Subsequently, solid-pha se direct sequencing of the alpha-Gal A gene demonstrated a novel single ba se deletion in exon 1 (30delG), Discrepancies were observed between the enz ymatic and molecular diagnoses in two at-risk females. These findings empha size the need for precise heterozygote diagnosis by mutation and/or haploty pe analyses in all families with Fabry disease. Am. J, Med, Genet, 84:420-4 24, 1999, (C) 1999 Wiley-Liss, Inc.