High Prevalence of Genetic Etiologies in 105 Pediatric Patients with Manifestation of Severe and End-Stage Congestive Heart Failure—What Can We Learn?

Background: Infectious and metabolic diseases can cause pediatric congestive cardiac failure (CCF). The prevalence and contribution of genetic disorders are yet unproven. This retrospective study assessed early manifestation of CCF in children. Pathogenic DNA variants (ACMG class 4 or 5) and outcome were compared with results from biopsy examinations.

Method: Single-center analysis of all in-hospital pediatric patients (0–18 years) presenting with CCF. The primary endpoint was genetic testing of the patients by NGS sequencing (Illumina, TrueSight Cardio Panel). Clinical courses including conservative treatment, VAD-implantation and heart transplantation (HTx) as inclusion criteria were compared with genotype and data from endomyocardial biopsy (MB) testing for potentially infectious causes of CCF.

Results: A total of 105 (56 male) patients born between 1972 and 2021 met the inclusion criteria with dilative (n = 90), restrictive (n = 8), hypertrophic (n = 5), or arrhythmogenic (right) ventricular (n = 2) cardiomyopathy. Thirty-five (33.1%) were directly transplanted (HTx), 40 (36.2%) were bridged by VAD-implantation (BTT). Four patients died during VAD therapy, three are waiting for HTx, and six could be weaned. Seventeen patients are stable under pharmacological treatment. Twelve died after HTx, in four, treatment was not reasonable. Forty-four of 105 patients (41.9%) had pathogenic variants. We found ACMG 4-variants in 26 cases: 1xFKTN, 2xLMNA, 3xMYH7, 1xNOTCH1, 1xTAZ-p, 1xPKP2-homozygous, 1xTNNC1, 1xPTPN11, 5xTNNI3, 2xTNNT2, 2xTPM1, 5xTTN, 1xTTN+RBM20, and ACMG-5 variants in 18: 1xALMS1, 1xBMG3, 1xDES, 1xDMD, 5xMYBPC3, 2xMYH7, 1xRBM20, 2xTNNI3, 3xTNNT2, and 1xTTR. Family testing revealed a high proportion of de novo mutations (23.5%). In 20/44 cases (45.5%), histological findings of myocarditis were found. Seventy-five patients had MB, in 48 (64%), signs for acute (n = 5), chronic (n = 27), nonspecific (n = 15), or eosinophilic (n = 1) myocarditis were found. In 17 myocarditis cases (35.4%), ACMG-4,-5 mutations were identified.

Conclusion: In this large series of pediatric CCF patients, clinical outcome with the destination HTX or BTT was excellent with only four deaths. The proportion of cases with pathogenic genotypes is remarkably high. The spectrum of affected genes differs considerably from adult nonischemic patients. De novo mutations play a substantial role. In severe forms of CCF pathological examination and genetic testing is highly recommended to allow proper counseling of affected families.

Publication History

Article published online:
12 February 2022