CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 5, September/October 2022 284 AFRICA The second heterozygous single-nucleotide variation, c.5668G>A, is registered on the Atlas of Genetic Cardiac Variation database, with an uncertain clinical significance, likely associated with dilated cardiomyopathy (DCM). The G>A nucleotide change in codon 1890 leads to an amino acid change of glutamic acid (Glu) to lycine (Lys) (p.E1890K) (Fig. 4). This variant is considered by 87.5% of algorithms to be likely damaging, predicting an adverse effect on the protein structure. The E1890K variant is a non-conservative amino acid substitution, which would likely impact on the secondary protein structure as these residues differ in polarity, charge, size and/ or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis, predicts this variant to be probably damaging to the protein structure/function. More recently, p.E1890Khas been registered on the NCBI database under rs766875593, with an uncertain clinical significance associated with various channelopathies rather than a cardiomyopathy. Recent studies reported on the identification of this variant in SUID cases associated with the long-QT syndrome (LQTS) as well as Brugada syndrome (BrS). The Genome Aggregation Database (gnomAD) and the Exome Aggregation Consortium (ExAC) reported on an allele frequency of 0.00001 and 0.00002, respectively. However, it is important to note that these allele frequencies are not representative of the African population since no studies have been done to provide statistics on this occurrence. Wang et al.14 reported on the identification of this variant in a two-month-old infant, whose cause of death could not be determined after a thorough autopsy, scene investigation as well as all ancillary investigations had been conducted. A review of the case history indicated a prone sleeping position at the time of death, with a history of a recent cold, similar to our case study. Discussion Two heterozygous missense variations in the SCN5A gene were identified in this SUID. Bearing in mind that a cause of death (bacterial pneumonia) had been established for this case prior to genetic testing, the results were deemed significant, although unexpected, in explaining the full circumstances surrounding the death. The SCN5A gene encodes a protein, sodium (Nav1.5) ion channel pore-forming α-subunit, that is expressed only in the myocardium and performs a critical role in heart excitability and conduction.15-17 The integral membrane protein produces the fastinward Na+ current that is responsible for the depolarising phase of the cardiac action potential. Variations in this gene cause an increased persistent Na+ current, with a subsequent prolongation of the ventricular action potential, essentially resulting in an inherited predisposition to ventricular arrhythmias and sudden death, seen in several cardiac diseases.4,18 Previous studies demonstrated a link between SUIDand a predominance of SCN5A variants, more commonly associated with channelopathies. Channelopathies are generally described as inherited cardiac arrhythmogenic disorders associated with isolated electric dysfunction caused by variants in genes encoding for cardiac ion channels and regulatory protein receptors, which are involved in the ionic control of the cardiac action potential.1,14 A link between many human diseases and the dysfunction of ion channels (channelopathies) has been established, either as a result of genetic variants or acquired malfunctions of ion channels.13,17 The threemost commonand epidemiologically relevant genetic heart channelopathies include LQTS, BrS and catecholaminergic polymorphic ventricular tachycardia (CPVT).1,13,14 Although the involvement of numerous susceptibility genes has been identified, most of the variants (especially in SUID cases) have been located in the SCN5A gene, predominantly linked to LQTS and BrS.13-15 Post mortem genetic studies have implicated channelopathyassociated variants in 10 to 15% of SUID cases.1,8,14 The most common clinical manifestations associated with LQTS and BrS are syncope, seizures and sudden death as a result of ventricular arrhythmias, usually occurring during a period of rest/sleep. Of particular note is that these channelopathyrelated sudden deaths generally present with no macroscopically identifiable structural alterations of the heart at autopsy.4,8,15,16 Our case study was found to carry two variations, of which one has been documented with an uncertain clinical significance, although associated with LQTS, BrS and DCM. Numerous studies have reported on the diversity of the phenotypic and genotypic expression of the SCN5A gene with variations linked to other arrhythmogenic disorders, including DCM, progressive familial heart block type 1 and sick sinus syndrome.8,16,19 Reports of SUID cases where genetic variations associated with cardiomyopathies are increasingly identified in structurally normal hearts should prevent the tendency of eliminating associations between SCN5A variations and DCM.1,8,20-22 Cardiomyopathies can be described as a group of heart diseases that affect the structure and function of the myocardium, which can all lead to heart failure, arrhythmia and even sudden death.9,12,23 The most common types of cardiomyopathies include hypertrophic cardiomyopathy, DCM, restrictive cardiomyopathy and arrhythmogenic cardiomyopathy.12,21,23 Although it is generally associated with cardiac alterations macroscopically identifiable at autopsy, it is not uncommon for a cardiomyopathy to be inadvertently missed in SUID cases, which usually present with a macroscopically normal heart.1,8,22,23 Studies have been reported that genetic variations in cardiomyopathy-related genes, which may cause arrhythmia and sudden death, have been identified in SUID cases presenting Fig. 3. Heterozygous single-nucleotide variation p.A1856T (c.5566G>A) identified in exon 28 of the SCN5A gene. Fig. 4. Heterozygous single-nucleotide variation p.E1890K (c.5668G>A) identified in exon 28 of the SCN5A gene.
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