High Prevalence of Genetic Alterations in Infantile-Onset Cardiomyopathy

Abstract

Background and Method: The genetic cause of infantile-onset cardiomyopathy is rarely investigated. Here, we conducted whole exome sequencing (WES) and mitochondrial DNA (mtDNA) sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations. Result: Among these patients, two (25%) had dilated cardiomyopathy (DCMP), two (25%) had left ventricular non-compaction (LVNC), and four (50%) had hypertrophic cardiomyopathy (HCMP). Except four patients identified prenatally, the remaining patients presented at a median age of 85.5 days. WES identified genetic variants in a total of seven (87.5%) patients and mtDNA sequencing in the other case. TPM1 and MYH7 variants were identified in the two patients with DCMP; MYH11 and MYLK2 variants in the two patients with LVNC; HRAS, BRAF, and MYH7 variants in three patients with HCMP; and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels. Among the eight variants, four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics (ACMG) guidelines, and the remaining were identified as variants of unknown significance (VUSs). Three pathogenic mutations were de novo, whereas four (likely-pathogenic or VUSs) were inherited from a respective parent, excluding one variant where parental testing was unavailable, questioning whether these inherited variants are disease-causing. Three patients died before 3 months of age. Conclusion: Genomic studies, such as WES with additional mtDNA sequencing, can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy. The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.