GLA variation p.E66Q identified as the genetic etiology of Fabry disease using exome sequencing.

Fabry disease (FD) was an X-linked lysosomal storage disorder resulting from a deficiency in glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene GLA. Variant FD patients did not present with classical symptoms during childhood and were undiagnosed or misdiagnosed with other kidney diseases, such as chronic glomerulonephritis (CGN). In this study, we utilized exome sequencing and Sanger sequencing identified the variation p.E66Q of GLA completely co-segregated with the disease phenotype in a Chinese family, which previously been diagnosed as possible CGN. Female patients exhibited preferential X-chromosome inactivation (XCI) of the normal p.E66 allele, as indicated by XCI analysis. By measuring α-Gal A activity, we found that male patients in the pedigree had just little enzymatic activity while female patients had residual enzymatic activity. These patients were diagnosed with renal variant FD in subsequent clinical review. Our results directly implicated the GLA mutation p.E66Q as the genetic etiology of the Chinese renal variant FD pedigree.