Why use genetic testing?

In patients with Fabry disease, variants in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A) lead to alterations or a reduction in enzyme activity.1 Deficient activity of α-Gal A leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) within almost all cell types and various organs.2-4 Assessing α-Gal A enzyme activity can be used to confirm a diagnosis of Fabry disease in males.5-8 However, the α-Gal A enzyme assay is considered less reliable for diagnosing Fabry disease in females because many patients exhibit enzyme activity levels comparable with those in unaffected individuals without Fabry disease.5,6 Genetic testing is therefore used to confirm a diagnosis of Fabry disease in female patients, and can be used to support a diagnosis in males.5-8

What is genetic testing for Fabry disease?
More than 1000 variants in the GLA gene leading to a deficiency of α-Gal A activity have been identified.9,10 GLA variants may be attributed to classical or late-onset Fabry disease (see genetic inheritance); many variants have also been categorised on fabry-database.org.11,12 The majority of GLA variants are private, occurring in single or a few families.12,13 Although, even in the same families with the same GLA variant, disease manifestations of Fabry disease can vary between patients.14 To identify Fabry disease-related variants, it is considered necessary to sequence the whole GLA gene and flanking regions.15 Genomic DNA can be extracted from peripheral-blood lymphocytes or dried blood spots using standardised protocols.16,17 In some instances, conventional genomic sequencing may not identify familial variants in the gene coding or flanking region, and microarray-based duplication or deletion testing of the GLA gene may be used.15 Moreover, standard GLA sequencing techniques may not detect large deletions, large duplications, some intronic variants, and variants in the promoter region or other regulatory regions. The results of GLA sequencing must therefore be interpreted in the context of a patient’s individual clinical and biochemical profile.15 GLA gene sequencing results should be analysed by an expert and it is recommend that genetic counselling be offered to patients.18 Following a diagnosis of Fabry disease, a thorough pedigree analysis should be performed to identify any at-risk family members (see family screening).15,18

C-ANPROM/INT/FAB/0016; Date of preparation: March 2021