Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death

Abstract

Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death.

Primary carnitine deficiency in two sisters with intractable epilepsy and reversible metabolic cardiomyopathy: Two case reports

“…A high dose levocarnitine treatment may cause diarrhea, nausea and other gastrointestinal discomforts; however, the dose can be reduced and once the adverse reactions have improved, it can be gradually increased to the initial treatment dose (20). Patients with PCD require a lifelong treatment with levocarnitine, and a sudden withdrawal may result in a rapid drop in the plasma carnitine concentration, causing recurrent Reye syndrome and even sudden death (21). For asymptomatic patients with PCD, treatment with levocarnitine has been indicated to be effective in preventing morbidity and sudden death (22).…”

Noncardiac genetic predisposition in sudden infant death syndrome

“…Our current study now examines the potential contribution of "non-cardiac" genes in the pathogenesis of SIDS using a similar approach to examine 61 published non-cardiac genes previously implicated in SIDS 8,[17][18][19][20][21] . The majority had been identified as potential "SIDS-susceptibility" genes following both common and rare variant association studies, typically involving promoter region variants.…”

“…8 Based on our own literature search of articles from 2014 to 2018, 6 additional SIDS-susceptibility genes were included for a total list of 61 non-cardiac, candidate genes (see Online Supplement eTable 1). [17][18][19][20][21] Following exome sequencing, single nucleotide variants (SNVs) and insertion/deletions (INDELs) were filtered to identify variants which followed either a dominant or recessive inheritance pattern using Ingenuity Variant Software (Qiagen, Redwood City, CA). All variants within the 61 non-cardiac SIDS-susceptibility genes were first filtered for a call quality score ≥ 20 and a read depth ≥ 10.…”

Overview of the Components of Cardiac Metabolism

“…Recent genetic analysis has linked a human biallelic variant in the SLC22A5 gene encoding the OCT2 with pediatric cardiomyopathy that is responsive to exogenously administered carnitine (Lahrouchi et al, 2017). Others have found variants of SLC22A17 and SLC22A7 to be predictive markers of anthracycline cardiotoxicity (Visscher et al, 2015).…”