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

Abstract

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

Opportunities and challenges for newborn screening and early diagnosis of rare diseases in Latin America

“…Beyond individual outcomes, an early and accurate diagnosis remains imperative for epidemiology and planning for healthcare systems ( Esquivel-Sada and Nguyen, 2018 ). Studies have demonstrated the utility of early and precise molecular diagnoses of newborns and children with RD to guide treatment and improve patient outcomes in the healthcare system ( Pezzoli et al, 2021 ; Smedley et al, 2021 ).…”

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

“…The correlation with LVNC has been corroborated by Mehaney et al [ 34 ], who reported the case of a 7-year-old male patient who was diagnosed at the age of 6 months with an overlapping phenotype of LVNC and DCM, and presented with a homozygous c.258del (p.Leu88Trpfs*27) mutation. The two distinct case series published in 2021 by Seidel et al [ 35 ] and Pezzoli et al [ 36 ] further consolidated the p.Arg69Alafs* and c.24+2T>A mutations as recurrent causes of early onset autosomal recessive DCM in four unrelated patients; notably, Seidel’s study was performed on a selected cohort of myocarditis patients, as was the case of Belkaya’s. Janin et al [ 37 ] reported the most extensive case series to date, supplemented by a very accurate phenotypic characterization.…”

Chung–Jansen syndrome can mimic Cornelia de Lange syndrome: Another player among chromatinopathies?

“…Two pipelines were used to identify the copy number variants (CNVs) based on ExomeDepth and one created in‐house, as previously described (Pezzoli et al, 2021). All the CNVs detected by both pipelines were annotated by matching every call with the genes involved and related diseases and classified according to ACMG and ClinGen guidelines (Riggs et al, 2020).…”