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Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later‐onset GLA mutation c.936+919G>A (IVS4+919G>A)
Author(s) -
Hwu WuhLiang,
Chien YinHsiu,
Lee NiChung,
Chiang ShuChuan,
Dobrovolny Robert,
Huang AiChu,
Yeh HuiYing,
Chao MayChin,
Lin ShioJean,
Kitagawa Teruo,
Desnick Robert J.,
Hsu LiWen
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21074
Subject(s) - newborn screening , fabry disease , hum , biology , phenotype , mutation , compound heterozygosity , heterozygote advantage , disease , incidence (geometry) , dried blood spot , medicine , clinical phenotype , genetics , endocrinology , gene , allele , physics , optics , art , performance art , art history
Abstract 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.