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
Abstract
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.
Related
- Prenatal Diagnosis of Recurrent Fetal Intracranial Hemorrhage and a Maternally Inherited COL4A1 Variant of Uncertain Significance: A Case Report With Maternal Reverse Phenotyping
- Maternally inherited PRKAR1A pathogenic variant causing Carney complex with a concomitant LDLR variant resulting in hyperlipidemia: a case report
- Impaired Atrioventricular Conduction System in a Postoperative Heart With Congenitally Corrected Transposition of the Great Arteries
- Double-Inlet single ventricle associated with transposition of the great arteries, situs inversus, and criss-cross heart in an unrepaired adult: A case report
- Left-sided surgical approach for tricuspid valve replacement in congenitally corrected transposition of the great arteries with dextrocardia and situs inversus totalis: A case report.
BibTeX
@article{ahamed2026danon,
title = {{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}},
author = {Hisham Ahamed and Aparna Hari and Raman Krishna Kumar and Vidya Jha},
journal = {European Heart Journal. Case Reports},
year = {2026},
month = oct,
doi = {10.1093/ehjcr/ytag780},
url = {https://doi.org/10.1093/ehjcr/ytag780},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Hisham Ahamed
AU - Aparna Hari
AU - Raman Krishna Kumar
AU - Vidya Jha
PY - 2026
DA - 2026/10/26
JO - European Heart Journal. Case Reports
DO - 10.1093/ehjcr/ytag780
UR - https://doi.org/10.1093/ehjcr/ytag780
AB - 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.
SN - 2514-2119
ER -