Identification of an Ultra-Rare GLA Frameshift Variant in a South African Family With Hypertrophic Cardiomyopathy: A Case Report

Fabry disease (FD) is an X-linked deficiency in glycosphingolipid metabolism caused by pathogenic variation in <i>GLA</i>. FD can mimic hypertrophic cardiomyopathy (HCM). Here, we present a South African patient of European ancestry with HCM where subsequent genetic analysis led to a diagnosis of FD. He was diagnosed with HCM at the age of 53 when he presented with new-onset atrial fibrillation (AF) and a left occipital cerebral infarction. He reported receiving treatment for recurrent pneumothoraxes in his mid-20s and suffered a transient ischemic attack (TIA) seven years prior to his diagnosis. During follow-up, he developed progressive chronotropic incompetence with AF and symptomatic bradycardia requiring pacing, as well as progressive dyspnea with obstructive lung disease, mild proteinuria with grade 1 chronic kidney disease, and peripheral neuropathy. Genetic research led to the identification of a pathogenic frameshift variant (<i>GLA</i> c.774_775delAC; p.Pro259ArgfsTer5) in the patient and his mother. This is an ultra-rare 2 bp pathogenic deletion in the causative gene for FD. Therefore, a diagnosis of FD was considered in this family and subsequently confirmed by an enzyme activity test. The proband was started on enzyme replacement therapy (ERT) to preserve kidney function and prevent other organ involvement, although it was not expected to reverse cardiac hypertrophy. This case demonstrates that non-cardiac disease may precede cardiac presentation in FD, emphasizing the importance of a detailed medical history in patients presenting with HCM. Testing for <i>GLA</i> variation should be considered in patients with similar phenotypic presentation, as diagnosis of HCM phenocopies such as FD can have important implications on treatment and management. Timely treatment of FD with ERT is crucial to prevent end-stage organ damage and preserve quality of life.