Genetic Architecture of Pediatric Cardiomyopathies Assessed by Whole-Exome Sequencing: Insights Into Early-Onset and Syndromic Forms.

Heterogeneous genetic architecture combining classical sarcomeric genes and syndromic cardiomyopathy genes, the latter over-represented in very early-onset forms.

Retrospective study (2018-2024) of 59 pediatric patients who underwent WES for cardiomyopathy at Amiens and Lille University Hospitals. WES identified at least one variant of interest in 62.7 % of patients (37/59), including 45.8 % (27/59) pathogenic or likely pathogenic variants and 16.9 % (10/59) variants of uncertain significance. Yield for variants of interest was 67.7 % in hypertrophic and 57.1 % in dilated forms, and was higher in children diagnosed before 1 year of age than later (72.7 % vs 56.7 %). Among patients diagnosed before 6 months, 55 % carried a variant in a gene associated with syndromic cardiomyopathy, including cases with an apparently isolated cardiac phenotype. The authors support WES as a first-line approach in pediatric cardiomyopathy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure that should change practice is that 55 % of forms diagnosed before 6 months involved a syndromic gene despite an apparently isolated cardiac phenotype: a cardiomyopathy panel ordered on cardiological presentation alone structurally misses these cases, which argues for genome-wide analysis as the first-line test in infants. The trade-off, visible here, is the rate of variants of uncertain significance (16.9 %): broadening the scope shifts the effort from sequencing to interpretation and family recall. With 59 patients from two centers and retrospective selection of indications, the 62.7 % yield is likely higher than what an unselected flow would give.

Analysis by Dr Thibaut Benquey