Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses

Abstract

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant.

Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel.

Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively.

Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

Keywords: exome sequencing; gene panel; hypertrophic; pediatric cardiomyopathy; sudden cardiac death.

Figure 1

Study design and work-flow in our study. In the original young hypertrophic cardiomyopathy (HCM)-population, nearly 75% were found to carry a previous known HCM-causative genetic mutation. With the present strategy there was a result of a genetic variant interpreted as pathogenic in 5 families, i.e., 50% of the population and genetic variants of unknown significance (VUS) in additional 30%. Only in two families did this strategy fail to find the underlying genetics.

Figure 2

Pedigree of the families in this study. Circles in the pedigree denote females, squares males. A crossed-over symbol indicates that the particular individual has died. The arrow points out the index patient in each family. The autosomal dominant genetic variant detected in each family is indicated with a ‘+’ sign if the individual is a carrier. The black color filling indicates clinical disease presentation. Of note, in Family 6 there is the autosomal recessive disorder PGM1-CDG, where the black color filling show homozygous patients with clinical disease, and half-filling represent heterozygous asymptomatic carriers.

Figure 3

Index patient, Family 1, ECG (A) and the echocardiogram, apical 4-chamber view (B) at the age of 12 years.

Figure 4

ECG of the index patient, Family 10. (A) ECG at the age of 24 years. (B) ECG at the age of 14 years when visited the emergency department because of a fainting episode after playing hockey.

Figure 5

Index patient, Family 3, ECG at the age of 14 years with prolonged QTc. At this time, the echocardiogram revealed only mild left ventricular hypertrophy.

Figure 6

Echocardiogram preoperative in neonatal period of the index-patient, Family 5, left ventricular outflow tract obstruction (LVOTO) and left ventricular hypertrophy (LVH) in long axis view (A) and short axis view (B). Arrow located in the left ventricular outflow tract with accessory material creating a severe LVOTO (A), arrow also at the level of the aortic valve, while arrow in (B) are localized in the hypertrophied interventricular septum.