Danon disease due to a de novo LAMP2 variant in a girl with d-transposition of the great arteries and a maternally inherited GDF1 variant: a case report

Danon disease, caused by loss-of-function variants in LAMP2, is an X-linked cardioskeletal disorder with cardiac manifestations in heterozygous females that are often underrecognized. The co-occurrence of surgically corrected dextro-transposition of the great arteries (d-TGA) and subsequent Danon cardiomyopathy in a patient carrying a maternally inherited GDF1 variant of uncertain significance has not previously been reported.

We describe a girl with d-TGA repaired in the neonatal period who later presented at 12 years of age with progressive dyspnoea on exertion (New York Heart Association class III). She was found to have severe left ventricular hypertrophy (LVH), biventricular outflow tract obstruction, myocardial fibrosis, and non-sustained ventricular tachycardia on ambulatory electrocardiographic (ECG) monitoring. Whole-exome sequencing revealed a de novo pathogenic LAMP2 variant, c.98del (p.Leu33Ter), predicted to disrupt all LAMP2 isoforms, establishing the diagnosis of Danon disease. A maternally inherited GDF1 in-frame deletion, c.651_656del (p.Ala218_Leu219del), was also identified and classified as a variant of uncertain significance; while its clinical significance remains unresolved, it is biologically plausible that the GDF1 variant may have contributed to the congenital heart disease substrate.

This case highlights two mechanistically distinct genetic events operating across different developmental windows: a likely susceptibility allele for congenital heart disease and a de novo lysosomal cardiomyopathy causing Danon disease. In patients with repaired congenital heart disease who subsequently develop an otherwise unexplained hypertrophic cardiomyopathy (HCM) phenotype, comprehensive cardiomyopathy-focused genetic evaluation may reveal a second diagnosis with major prognostic, therapeutic, and family-screening implications.