Background and Aim:

Hypertrophic cardiomyopathy (HCM) may cause heart failure and sudden cardiac death. Assessing its genetic cause might be important for diagnosis and further therapy. Generally, in 60% of children pathogenic variants are found, in the remaining cases the genetic cause is unclear. We present a case of a consanguine family with rare genetic background.

Methods:

We performed whole-exome sequencing (WES) of an 11-years-old girl with HCM, her consanguine parents, and an older sister. WES data were filtered for rare (minor allele frequency <10^-4) likely pathogenic or pathogenic (L)P genetic variants. Endomyocardial biopsy (EMB) samples of the index patient were analyzed histologically and with immunostaining.

Results:

The girl presented with HCM, left ventricular (LV) outflow obstruction, ventricular tachycardia, and severe heart failure with cardiac decompensation. The LV ejection fraction was 25%. NT-proBNP level and Troponin Ihs levels were elevated with 25940 ng/l and 240 pg/nl, respectively. Accordingly, the patient required biventricular assist device implantation and heart transplantation. Her father was also affected and heart transplanted. WES of the family identified three homozygous variants in the index patient: 1) a (L)P missense variant in dihydropyrimidinase (DPYS, p.S379R) causing pyrimidine deficiency; 2) a (L)P non-sense variant in patatin like phospholipase domain containing 2 (PNPLA2, p.L205Pfs*102) resulting in defective triglyceride metabolism, lipid storage disease, and myopathy; 3) a truncating variant in Kelch like family member 24 (KLHL24, p.T496Kfs*5) classified as VUS. Mutation of KLHL24 was recently linked to HCM with glycogen storage disease. The affected father also carried the homozygous variant in KLHL24 suggesting this genetic alteration as primary disease cause. EMB of the index patient showed diffuse, focal, and perivascular fibrosis. Myocardial cardiomyocytes were hypertrophic, irregularly structured, and showed enlarged nuclei. Very noticeable were many cytoplasmatic small vacuoles in the cardiomyocytes. These vacuoles were Oil Red staining positive suggesting them as fat vacuoles. The EMB PAS staining identified increased intercalated polysaccharides e.g., glycogen.

Conclusions:

This is a rare autosomal recessive familial HCM leading to characteristic histopathological changes in EMB with increased glycogen and lipid storage highlighting the importance of storage diseases as potential cause of HCM. This case report undermines that homozygous mutation of KLHL24 leads to HCM and demonstrates unexpectedly early manifestation of cardiac lipid deposition in homozygous PNPLA2 myopathy.