Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

Figures

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  Figure 1. Measurement of turnaround time (TAT) of WES analysis in urgent and non-urgent settings. T1: time to preliminary result, T2: time to definitive report.

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  Figure 2. Clinical presentation and genetic findings of the patient with HCCS variant. (A) Trio-WES identified a de novo variant (NM_ 005333.4:c.522-12G>A) in HCCS gene (OMIM * 300056), predicted to create a new splice-site 12 bases upstream the canonical acceptor site of exon 6 (B). (C) Two-dimensional echocardiogram of patient #14 at birth (1) and 1 month later (2), showing mild left ventricular hypertrophy and dilation with apical non-compaction and mild mitral valve insufficiency, with normal right ventricle function and volumetry. Electrocardiogram (3) and echocardiogram (4) at 6 months of age, showing severe left ventricular dysfunction with a “foamy” appearance of the myocardium.

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  Figure 3. Clinical presentation and cTnI tissue levels of patients with homozygous TNNI3 (OMIM *191044) variants. (A) Clinical data at admission of patient #8. (B) Two-dimensional echocardiogram of patient #8, showing a dilated left ventricle and left atrium, with rightward shift of the interatrial and interventricular septum and thin left free-walls. (C) Electrocardiogram of patient #8, showing low-voltage QRS complexes in inferior and lateral leads, no R wave progression in leads V1–V3 and T-wave inversion in leads V4–V6. (D) Histograms showing the tissue level of cTnI, myoglobin (MYO), muscular isoforms of creatine kinase (CK-MB) and aspartate aminotransferase (AST) in myocardial specimens from explanted frozen left ventricle of patient #41, her affected sister and three negative controls. F1-III3, patient #41; F1-III2, affected sister of patient #41; C1, age-matched hypertrophic cardiomyopathy patient; C2, age-matched idiopathic dilated cardiomyopathy patient; C3, adult ischemic cardiomyopathy patient. Abbreviations: LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium; EDD, end-diastolic dimension; FS, fractional shortening; PWT, posterior wall thickness; SWT,…

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  Figure 4. De novo duplication of the ATAD3 gene cluster (OMIM #618815) identified in a female newborn with left ventricle hypertrophy and clinical suspicion of mitochondrial disease. (A) In a newborn female presenting with brain anomalies, left ventricular hypertrophy and corneal opacity, leading to the clinical suspicion of mitochondrial disease, we identified a previously reported de novo duplication in the ATAD3 gene cluster (chr1:1392270_1460317dup), which creates an ATAD3A-C fusion gene (B). The presence of the duplication has been confirmed by PCR (C) using the same primers reported by Gunning et al. [25] for case 4 (* F: chr1 (GRCh37):1459103-1459123 and * R: chr1 (GRCh37):1392608-1392630).

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  Figure 5. Flowchart describing the main results of trio-WES analysis in infantile cardiomyopathies, performed in urgent (A) and non-urgent (B) settings; * 1 patient underwent liver transplantation (tyrosinemia).