Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure. Parent-offspring whole exome sequencing (WES) data were filtered for rare, deleterious, de novo and recessive variants. In prior work, we reported de novo mutations in TNNT2 and RRAGC and compound heterozygous mutations in ALMS1 and TAF1A among four cases in our cohort. Here, de novo mutations in established DCM genes—RBM20, LMNA, TNNT2, and PRDM16—were identified among five additional cases. The RBM20 mutation was previously reported in familial DCM. An identical unreported LMNA mutation was identified in two unrelated cases, both harboring gene-specific defects in cardiomyocyte nuclear morphology. Collectively, WES had a 50% diagnostic yield in our cohort, providing an explanation for pediatric heart failure and enabling informed family planning. Research is ongoing to discover novel DCM genes among the remaining families.

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

“…In the literature, no fetus has been reported to have variants in PRDM16, but early-onset pediatric cases have been reported. The youngest patient (4 months) was reported by Long, Evans, & Olson (2017). He carried a de novo frameshift Ser350fs*48 variant and had DCM with mild features of LVNC.…”

“…Coordinates are based on human genome build GRCh37/hg19. Location of amino acid changes reported in the literature (Arndt et al, 2013, Long et al, 2017, and van Waning et al, 2018 According to the ACMG recommendations, this variant has been classified as pathogenic.…”

“…Coordinates are based on human genome build GRCh37/hg19. Location of amino acid changes reported in the literature (Arndt et al, , Long et al, , and van Waning et al, ) in LVNC are in black and in DCM are in gray. The de novo mutation of our case is in red.…”

Inferring the effect of genomic variation in the new era of genomics

“…Numerous deleterious variants were identified, especially in the TP53 (MIM# 191170) gene. In contrast, the clinical diagnostic yield of ES varies highly, ranging from 25% to 60% of selected cases depending on number, ethnicity, trio (both parents and proband) or singleton sequencing, and disease cohort, with exceptional rate of finding de novo variants by trio sequencing across both rare and more common diseases (Dragojlovic et al., ; Long, Evans, & Olson, ; Parsons et al., ; Rossi et al., ; Samocha et al., ; Trujillano et al., ; Vissers et al., ; Yang et al., ; Yavarna et al., ). ES is now a specialized diagnostic screen for disease candidate genes since each ES can provide ∼30,000 variants in the coding regions that can then be filtered to identify the most relevant (Gilissen, Hoischen, Brunner, & Veltman, ).…”

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

“…RBM20 was itself first identified in a search for a familial genetic basis of DCM in human patients (Brauch et al, 2009). Subsequent investigation has identified additional patients and mutations involving RBM20 related to DCM (Zhao et al, 2015b;Long et al, 2017;Wells et al, 2013;Waldmüller et al, 2015;Chami et al, 2014;Refaat et al, 2012;Rampersaud et al, 2011;Millat et al, 2011;Li et al, 2010;Robyns et al, 2019), as well as cardiac arrhythmia (Nielsen et al, 2018;Parikh et al, 2019), pediatric restrictive cardiomyopathy (Rindler et al, 2017) and left-ventricular non-compaction . Although representing only 3 % of idiopathic cases, patients with DCM that have mutant RBM20 correlate with earlier disease onset, high penetrance, and requirement for heart transplantation (Brauch et al, 2009;Li et al, 2010;Kayvanpour et al, 2017;Wells et al, 2013;Hey et al, 2019).…”