Cardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in GNPTAB

Background: Homozygous or compound heterozygous loss-of-function variants in GNPTAB cause mucolipidosis type II/III, a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. ML III is milder, with an older age of onset and a less severe phenotype. We report two siblings with arrhythmogenic cardiomyopathy and ventricular arrhythmias with compound heterozygous variants in GNPTAB. Methods and Results: The family presented due to the sudden cardiac death of a male in his early 30’s with arrhythmogenic cardiomyopathy identified at autopsy. His sister was found to have cardiomyopathy and experienced a ventricular tachycardia storm. Both siblings had history of skeletal dysplasia first investigated during adolescence. Clinical genetic testing did not identify a cause for the cardiomyopathy, and they were enrolled in the Elusive Hearts study. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5( GNPTAB ): c.3503_3504del, and a heterozygous missense variant, NM_024312.5( GNPTAB ): c.1400A>G, p.(Asp467Gly), occurring in trans . Enzymatic testing showed elevated plasma lysosomal enzyme activity, confirming the clinical diagnosis. Cardiomyopathy has rarely been reported in patients with ML III. Conclusion: We expand the cardiac phenotypic features of ML III and suggest that GNPTAB could be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest.