TY - JOUR
T1 - Low frequency of Fabry disease in patients with common heart disease
AU - Schiffmann, Raphael
AU - Swift, Caren
AU - McNeill, Nathan
AU - Benjamin, Elfrida R.
AU - Castelli, Jeffrey P.
AU - Barth, Jay
AU - Sweetman, Lawrence
AU - Wang, Xuan
AU - Wu, Xiaoyang
N1 - Funding Information:
R.S. has received research funding from Amicus Therapeutics, Protalix Biotherapeutics, Shire, and Sanofi Genzyme. E.R.B., J.P.C., J.B., and X. Wu are employees of Amicus Therapeutics. The other authors declare no conflict of interest.
Funding Information:
This work is supported in part by Baylor Research Institute Foundation, Amicus Therapeutics, Inc., and the National Institutes of Health U54 NS065768 (project LDN 6711). The Lysosomal Disease Network (U54NS065768) is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, and the National Center for Advancing Translational Sciences. This consortium is funded through collaboration between the National Center for Advancing Translational Sciences, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes and Digestive and Kidney Diseases. We thank David J. Lockhart for his support of this study and key insights and Marie-Anne Schiffmann for editing and proofreading the manuscript.
Publisher Copyright:
© 2017 American College of Medical Genetics and Genomics.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Purpose: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease. Methods: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing. Results: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5′UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5′UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81-77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease. Conclusion: This population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.
AB - Purpose: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease. Methods: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing. Results: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5′UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5′UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81-77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease. Conclusion: This population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.
KW - Fabry disease
KW - X-linked
KW - heart disease
KW - screening
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U2 - 10.1038/gim.2017.175
DO - 10.1038/gim.2017.175
M3 - Article
C2 - 29227985
AN - SCOPUS:85049873419
SN - 1098-3600
VL - 20
SP - 754
EP - 759
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -