Gene Mutations Versus Clinically Relevant Phenotypes

Author:

Niemann Markus1,Rolfs Arndt1,Störk Stefan1,Bijnens Bart1,Breunig Frank1,Beer Meinrad1,Ertl Georg1,Wanner Christoph1,Weidemann Frank1

Affiliation:

1. From the Department of Internal Medicine I (M.N., S.S., F.B., G.E., C.W., F.W.), Comprehensive Heart Failure Center (M.N., S.S., F.B., M.B., G.E., C.W., F.W.), Institute of Radiology (M.B.), University of Würzburg, Würzburg, Germany; The Albrecht-Kossel Institute for Neuroregeneration, University of Rostock, Rostock, Germany (A.R.); and ICREA-Universitat Pompeu Fabra, Barcelona, Spain (B.B.).

Abstract

Background— Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk. Methods and Results— A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7ng/mL suggested classical Fabry mutations in most of the patients (93%). Conclusions— Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Genetics (clinical),Cardiology and Cardiovascular Medicine,Genetics

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