Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later‐onset GLA mutation c.936+919G>A (IVS4+919G>A)

Fabry disease (α‐galactosidase A (α‐Gal A, GLA) deficiency) is a panethnic inborn error of glycosphingolipid metabolism. Because optimal therapeutic outcomes depend on early intervention, a pilot program was designed to assess newborn screening for this disease in 171,977 consecutive Taiwanese newborns by measuring their dry blood spot (DBS) α‐Gal A activities and β‐galactosidase/α‐Gal A ratios. Of the 90,288 male screenees, 638 (0.7%) had DBS α‐Gal A activity <30% of normal mean and/or activity ratios >10. A second DBS assay reduced these to 91 (0.1%). Of these, 11 (including twins) had <5% (Group‐A), 64 had 5–30% (Group‐B), and 11 had >30% (Group‐C) of mean normal leukocyte α‐Gal A activity. All 11 Group‐A, 61 Group‐B, and 1 Group‐C males had GLA gene mutations. Surprisingly, 86% had the later‐onset cryptic splice mutation c.936+919G>A (also called IVS4+919G>A). In contrast, screening 81,689 females detected two heterozygotes. The novel mutations were expressed in vitro, predicting their classical or later‐onset phenotypes. Newborn screening identified a surprisingly high frequency of Taiwanese males with Fabry disease (∼1 in 1,250), 86% having the IVS4+919G>A mutation previously found in later‐onset cardiac phenotype patients. Further studies of the IVS4 later‐onset phenotype will determine its natural history and optimal timing for therapeutic intervention. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.