Key result
Whole-exome sequencing identifies de novo LAMP2 variant causing Danon cardiomyopathy in repaired d-TGA.
Why the study?
Cardiac manifestations of Danon disease are often underrecognized in heterozygous females, and the co-occurrence of surgically corrected d-TGA and subsequent Danon cardiomyopathy in a patient carrying a maternally inherited GDF1 variant of uncertain significance had not previously been reported.
Case Report (n=1)
No
In patients with repaired congenital heart disease who develop an unexplained hypertrophic cardiomyopathy phenotype, comprehensive genetic evaluation can identify a distinct second genetic diagnosis such as Danon disease, which carries major prognostic, therapeutic, and family-screening implications.
Supports genetic evaluation for Danon disease in unexplained post-repair HCM; leaves open broader validation of dual genetic diagnoses.
Background 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. Case Summary 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. Discussion 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.
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Ahamed et al. (2026) conducted a case report in Danon disease (LAMP2 variant) and surgically corrected dextro-transposition of the great arteries (d-TGA) (n=1). Whole-exome sequencing / De novo pathogenic LAMP2 variant (c.98del) and maternally inherited GDF1 variant (c.651_656del) was evaluated on Diagnosis of Danon disease and hypertrophic cardiomyopathy phenotype. Whole-exome sequencing identified a de novo LAMP2 variant (c.98del) causing Danon cardiomyopathy and a maternal GDF1 variant in a 12-year-old girl with repaired d-TGA.
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