Genetic Basis of Severe Childhood-Onset Cardiomyopathies

Vasilescu, Catalina; Ojala, Tiina; Brilhante, Virginia; Ojanen, Simo; Hinterding, Helena M.; Palin, Eino; Alastalo, Tero-Pekka; Koskenvuo, Juha; Hiippala, Anita; Jokinen, Eero; Jahnukainen, Timo; Lohi, Jouko; Pihkala, Jaana; Tyni, Tiina; Carroll, Christopher J.; Suomalainen, Anu

doi:10.1016/j.jacc.2018.08.2171

Cited by 121 publications

(141 citation statements)

References 44 publications

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“…As mentioned above, it is also possible that our de novo rate is an underestimate as 14% of individuals with a P/LP variant and HCM had unknown inheritance status. One additional study reported a de novo variant in 46% of individuals specifically selected to represent severe disease, and included individuals with all cardiomyopathy phenotypes including syndromic disease and disease associated with primary arrhythmia syndromes (Vasilescu et al, ). The difference in rate of de novo variants in our study populations, 46% compared to 18%, is likely influenced by selection of severe disease and inclusion of syndromic cases in the cohort described by Vasilescu et al…”

Section: Discussionmentioning

confidence: 99%

“…An additional single center study reported identification of a de novo variant in 20% of pediatric patients with a disease‐causing variant associated with HCM (Mathew et al, ). A recent investigation of the genetic basis of severe childhood cardiomyopathy including individuals with syndromic disease identified a de novo variant in 46% of children with a pathogenic variant (Vasilescu et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Investigation of de novo variation in pediatric cardiomyopathy

Parrott

Khoury

Shikany

et al. 2020

American J of Med Genetics Pt C

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Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children with a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy (HCM, DCM, or RCM), and to compare disease outcomes between individuals with and without a de novo variant. A retrospective record review identified 126 individuals with HCM (55%), DCM (37%), or RCM (8%) ≤18 years of age who had genetic testing. Overall, 50 (40%) had positive genetic testing and 18% of P/LP variants occurred de novo. The rate of de novo variation in those with RCM (80%) was higher than in those with HCM (9%) or DCM (20%). There was evidence of germline mosaicism in one family with RCM. Individuals with de novo variants were more likely than those without to have a history of arrhythmia (p = .049), sudden cardiac arrest (p = .024), hospitalization (p = .041), and cardiac transplantation (p = .030). The likelihood of de novo variation and impact on family risk and screening should be integrated into genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigation of de novo variation in pediatric cardiomyopathy

Parrott

Khoury

Shikany

et al. 2020

American J of Med Genetics Pt C

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“…These included patients with extracardiac features or possible myocarditis. Other recent studies lead to the identification of pathogenic variants in 26% to 39% of pediatric patients . Our study suggests genetic testing for sarcomere gene variants in severely affected children as early as possible to support clinical decision making.…”

Section: Discussionmentioning

confidence: 54%

“…This approach allowed us to identify seven de novo variants (10%). This is a lower ratio of de novo variants than previously reported . Vasilescu et al reported 46% de novo variants in a cohort of infant childhood‐onset CMP (median age of diagnosis of 0.33 years) and 33% of individuals in this cohort presented with a systemic disorder.…”

Section: Discussionmentioning

confidence: 99%

“…There are only few studies on current genetic testing in pediatric CMP. Depending on the phenotypic composition of the cohorts, also including secondary CMP, and different next‐generation sequencing (NGS) strategies, recent studies lead to the identification of pathogenic variants in 26% to 39% of pediatric patients . These genetic defects exhibit variable expressivity and variable penetrance.…”

Section: Introductionmentioning

confidence: 99%

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Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

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COXPD9 in an individual from Puerto Rico and literature review

Alsharhan

Muraresku

Ganetzky

2021

American J of Med Genetics Pt A

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Defects of mitoribosome assembly with destabilization of mitochondrial ribosomal proteins and subsequent aberrant mitochondrial translation machinery are one of the emerging categories of human mitochondrial disease. Mitochondrial translation deficiency constitutes a growing cause of combined oxidative phosphorylation deficiency and overall causes a set of clinically heterogeneous multi-systemic diseases. We present here the sixth individual with combined oxidative phosphorylation deficiency-9 (COXPD9) secondary to a likely pathogenic homozygous MRPL3 variant c.571A > C; p.(Thr191Pro). MRPL3 encodes a large mitochondrial ribosome subunit protein,

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Genetic Basis of Severe Childhood-Onset Cardiomyopathies

Cited by 121 publications

References 44 publications

Investigation of de novo variation in pediatric cardiomyopathy

Investigation of de novo variation in pediatric cardiomyopathy

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

COXPD9 in an individual from Puerto Rico and literature review

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