Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy

Abstract

Background Pediatric dilated cardiomyopathy (DCM) is a well‐known clinical entity; however, phenotype–genotype correlations are inadequately described. Our objective was to provide genotype associations with life‐threatening cardiac outcomes in pediatric DCM probands. Methods and Results We performed a retrospective review of children with DCM at a large pediatric referral center (2007–2016), excluding syndromic, chemotherapy‐induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life‐threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, P =0.21). TTN truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, P =0.01), but life‐threatening cardiac outcomes occurred in both infants and teenagers with these TTN variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with MYH7 variants between amino acids 1 and 600. Conclusions Sarcomeric variants were common in pediatric DCM. We demonstrated genotype‐specific associations with age of diagnosis and cardiac outcomes. In particular, MYH7 had domain‐specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.

Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies

“…Controversial study results have been obtained with pediatric DCM. TTN and MYH7 mutations were identified as predominant in a cohort of 106 pediatric patients [74]. In another study analyzing 36 patients, only one TTN mutation, a truncation (p.Arg33703*), was identified in a 16-year-old male DCM patient [108].…”

“…DCM based on genetic defects seems to form the main cause of pediatric DCM, whereby the vast majority of gene mutations is found in sarcomeric proteins, especially in MYH7, TTN, TNNT2, TPM1, MYBPC3, MYL2, TNNC1 (Troponin C), and ACTN2. Others are found in LMN, DES, VCL (Vinculin), TTR (transthyretin), BAG3 (associated with apoptosis), MT-TS2 (encoding a mitochondrial small RNA), or transcription factor encoding PRDM16 [74][75][76][77][78]. In adult and pediatric DCM, the same genes seem to be affected, though unfortunately, most genetic testings have been performed in adults [79].…”

“…The location of mutations within MYH7 -another frequent target for pathogenic mutations -seems to determine the DCM type according to Khan et al [74]. They found that mostly single amino acid replacements in ß-Myosin heavy chain (MYH7) in the range of amino acids 1-600 lead to mixed DCM, a DCM-LNVC phenotype, whereas mutations in the C-terminal part from amino acid 600 lead to pure DCM [74]. The C-terminal rod of myosin heavy chain interacts with other myosin rods, which is essential to build up the thick filament.…”

A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches

“…Out of these 15 genes, 9 genes ( MYH7 , SCN5A , TNNT2 , LMNA , MYBPC3 , MYH6 , TNNC1 , TNNI3 and TPM1 ) are also known to cause DCM in adults. Recently, Khan et al [ 30 ] did a cohort study on 109 pediatric patients and found that TTN (Titin) truncation was the most prevalent cause of genetic DCM in pediatric patients. Along with TTN tv, genetic variations (mutation) were also detected in MYH7 among pediatric DCM patients.…”

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

“… 17 To date, DCM‐causing variations in >250 genes have been implicated with the development of DCM, of which the vast majority code for sarcomere proteins, nuclear envelope proteins, cytoskeleton proteins, Z‐band proteins, intercalated disc proteins, ion channel proteins, gap junction channel proteins, RNA‐binding proteins, mitochondrial proteins, and transcriptional factor proteins. 1 , 2 , 3 , 4 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 Additionally, genome‐wide association studies have led to the discovery of many new common variants involved in DCM, in addition to novel rare variants involved in DCM. 33 Nevertheless, the genetic architecture of DCM is highly complex and diverse owing to pronounced genetical heterogeneity, and the genetic determinants underpinning DCM in a large proportion of cases remain to be identified.…”