Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.

Congenital myotonia is a non-dystrophic musculoskeletal disease that causes abnormal muscle relaxation. The prevalence of congenital disorders is notably high in Iran, emphasizing the importance of genetic assessment in suspicious cases. In this study, we aim to report cases with the chloride channel gene, CLCN1, mutations leading to significant morbidity. This case report study investigated four patients from four families with clinically defined congenital myotonia. Inclusion criteria were increased creatinine kinase (CK) and muscle stiffness. We collected data regarding family history, age of onset, and current therapeutic plan. All patients underwent skeletal muscle electromyography, cardiological evaluation, spirometry study, and hematochemistry assessment, including but not limited to muscle enzyme levels. Afterward, DNA was extracted from peripheral blood. Subsequently, whole exome sequencing (WES) and Sanger sequencing were done to detect and confirm variants, respectively. Age of onset ranged from 1 to 12 years in these patients, which are years apart from their first visit to the clinic. The warm-up phenomenon was present in all of them. A variant of uncertain clinical significance was found. We recommend that future research projects should study the efficiency of collaboration between clinicians, molecular geneticists, and other healthcare providers in order to find out about unclear variants as quickly as possible.