The Phenotype and Outcome of Infantile Cardiomyopathy Caused by a Homozygous ELAC2 Mutation.

OBJECTIVE: Cardiomyopathy (CMP) in children is a clinically and genetically heterogeneous group of disorders. Disease-associated mutations have been identified in more than 50 genes. Recently, mutations in the mitochondrial tRNA processing gene, ELAC2, were reported to be associated with the recessively inherited form of hypertrophic CMP (HCM). This study is aimed at describing the cardiac phenotype and outcome of ELAC2 mutation. METHODS: We performed whole exome sequencing followed by targeted mutation screening to identify the genetic etiology of severe infantile-onset CMP in 64 consanguineous Saudi families. RESULTS: A previously reported mutation (p.Phe154Leu) in ELAC2 gene was detected in 16 families. The index cases presented between 2 and 7 months of age with HCM in 13 infants and dilated CMP (DCM) in 3. Pericardial effusion was observed in 7 infants (44%). All infants died with a median age of death of 4 months. Almost 1/3 of them died during the initial presentation. CONCLUSION: Our study suggests screening the ELAC2 gene in severe infantile-onset HCM or DCM of unknown etiology, especially in the presence of pericardial effusion. Our work demonstrates a universally poor outcome of the (p.Phe154Leu) variant in ELAC2 gene; a correlation that helps in counseling parents and in planning appropriate medical intervention.

A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy.

BACKGROUND: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM. METHODS: In a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect. RESULTS: A region of homozygosity (ROH) on chromosome 8q24.13-24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative. CONCLUSIONS: Our data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy.

Clinical and Genetic Characteristics of Arrhythmogenic Right Ventricular Cardiomyopathy Patients: A Single-Center Experience.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited progressive cardiomyopathy. We aimed to define the long-term clinical outcome and genetic characteristics of patients and family members with positive genetic tests for ARVC in a single tertiary care cardiac center in Saudi Arabia. Methods: We enrolled 46 subjects in the study, including 23 index-patients (probands) with ARVC based on the revised 2010 ARVC Task Force Criteria (TFC) and 23 family members who underwent a genetic test for the ARVC between 2016 and 2020. Results: Of the probands, 17 (73.9%) were males with a mean age at presentation of 24.95 ± 13.9 years (7 to 55 years). Predominant symptoms were palpitations in 14 patients (60.9%), and syncope in 10 patients (43.47%). Sustained ventricular tachycardia (VT) was documented in 12 patients (52.2%). The mean left ventricular ejection fraction (LVEF) by echocardiogram was 52.81±6.311% (30-55%), and the mean right ventricular ejection fraction (RVEF) by cardiac MRI was 41.3±11.37% (23-64%). Implantable cardioverter-defibrillator (ICD) implantation was performed in 17 patients (73.9%), and over a mean follow-up of 13.65 ± 6.83 years, appropriate ICD therapy was noted in 12 patients (52.2%). Genetic variants were identified in 33 subjects (71.7%), 16 patients and 17 family members, with the most common variant of plakophilin 2 (PKP2) in 27 subjects (81.8%). Conclusions: ARVC occurs during early adulthood in Saudi patients. It is associated with a significant arrhythmia burden in these patients. The PKP2 gene is the most common gene defect in Saudi patients, consistent with what is observed in other nations. We reported in this study two novel variants in PKP2 and desmocollin 2 (DSC2) genes. Genetic counseling is needed to include all first-degree family members for early diagnosis and management of the disease in our country.

Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity.

BACKGROUND: Congenital long QT syndrome (LQTS) is an inherited, potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70%, with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: To describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population. METHODS: Fifty-six Saudi families with LQTS were consecutively recruited and evaluated. Sequencing of KCNQ1, KCNH2, and SCN5A genes was conducted on all probands, followed by screening of family relatives. RESULTS: Genetic analysis was positive in 32 (57.2%) families, with mutations in KCNQ1 identified in 28 families (50%). Surprisingly, 17 (53.1%) probands were segregating homozygous mutations. Family screening identified 123 individuals with mutations; 89 (72.4%) were heterozygous, 23 (18.7%) were homozygous, and 11 (8.9%) were compound heterozygous. Compared to heterozygous, the phenotype was more severe in homozygous individuals, with cardiac symptoms in 78.3% (vs 12.4%), family history of sudden death in 64.7% (vs 44.4%), and prolonged QT interval in 100% (vs 43.8%). Congenital deafness was found in 11 (47.8%) homozygous probands. CONCLUSION: Our study provides insight into the clinical and molecular profiles of LQTS in a consanguineous population. It underscores the importance of preemptive management in homozygous patients with LQTS and the value of clinical and molecular screening of at-risk relatives.