A middle-aged female with idiopathic dilated cardiomyopathy (DCM) and a family history of premature sudden cardiac death was tested using the cardiomyopathy gene panel. We identified a class 3 variant in the
GLA gene (c.1153A>G; p.(Thr385Ala), NM_000169.2). The variant changes a moderately conserved amino acid (PolyPhen HumDiv = 0.708 and HumVar = 0.122) and the chemical difference between Thr and Ala is small (Grantham distance: 58 (0–215)). At the time of the test result this variant had not been described in over 10,000 control alleles. The
GLA gene on the X‑chromosome is one of the genes on the cardiomyopathy gene panel associated with a phenocopy of a cardiomyopathy. Pathogenic variants in the
GLA gene cause Fabry disease, a lysosomal storage disorder characterised by neuropathic pain, angiokeratoma, chronic kidney disease, left ventricular hypertrophy (mimicking hypertrophic cardiomyopathy (HCM)), and cerebrovascular disease. Left ventricular hypertrophy can also be the only disease expression, especially in female carriers, and in carriers of specific
GLA variants known to cause a cardiac-only phenotype. Patients suspected of HCM can have a
GLA variant and clinical Fabry disease. Our patient, however, did not have HCM but DCM and her variant was of unknown pathogenicity. Possible explanations included a) that the
GLA variant could be a new variant giving rise to a cardiac-only phenotype for Fabry disease; b) that our patient had Fabry disease with a DCM phenotype as an end-stage form of Fabry-related HCM/left ventricular hypertrophy [
12]; or c) that the variant should be regarded as an incidental finding unrelated to the patient’s phenotype. Because enzyme replacement can be effective in Fabry disease, we had to decide whether to evaluate our patient for other features of Fabry disease, and also, how to counsel the family. We discussed the test result with our patient and asked for more details on possible Fabry symptoms in her and other relatives. She did not have any other symptoms of Fabry disease and neither did any of her relatives. She had two brothers who died suddenly in their forties, which could fit with an X‑linked inheritance, but they were said to have no symptoms specific to Fabry disease. We therefore decided Fabry disease was unlikely and considered the
GLA variant an incidental finding. Because her DCM could still be hereditary, we advised regular cardiac evaluations for her first-degree relatives and the first-degree relatives of the sudden death victims in her family. Recently, this variant was reclassified to a class 2 variant (unlikely pathogenic). Reclassification was based on the frequency of this variant in controls with a similar ethnic background as our patient (53 times in 10,122 South Asian alleles) and a relatively high enzyme activity (45% of wild-type) in a functional study [
13].