The hunt for a genetic cause

Fabry disease is an X linked metabolic disorder due to a lack of the lysosomal enzyme alpha galactosidase A. Over 900 variants in the GLA gene are reported, the majority being private mutations restricted to individual families. Classic Fabry disease is the severe form of the condition. It is rare (incidence less than 1:100 000), arising from gene mutations that lead to zero enzymatic activity and has widespread systemic manifestations. By contrast, late-onset Fabry disease is much commoner and is characterised by missense mutations which are typically associated with up to 30% residual enzyme activity in males and often only affects a single organ system. Newborn screening programmes have revealed a high incidence of variants in GLA. Cardiomyopathy in adults is frequently the cardinal feature but associating this with particular genetic variants is confounded by criteria that ascribe their clinical consequence as benign, likely benign, likely pathogenic or pathogenic (American College of Medical Genetics and Genomics guidelines). Moreover, the increasing power of contemporary high-throughput sequencing technologies, which allows for longer reads and intronic/exonic boundaries to be interrogated, is uncovering genetic variants that increasingly shoulder the status of ‘variant of uncertain significance’ (VUS). So …