Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.

AIMS: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α-tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD. METHODS AND RESULTS: The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM. CONCLUSIONS: The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.

High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.

Pathophysiology, Diagnosis, Treatment, and Genetics of Carpal Tunnel Syndrome: A Review.

Carpal tunnel syndrome (CTS) is a common peripheral canalicular nerve entrapment syndrome in the upper extremities. The compression of or injury to the median nerve at the wrist as it passes through a space-limited osteofibrous carpal canal can cause CTS, resulting in hand pain and impaired function. The present paper reviews the literature on the prevalence, pathology, diagnosis, treatment, and risk factors of CTS in conjunction with the role of genetic factors in CTS etiology. CTS diagnosis is primarily linked with clinical symptoms; still, it is simplified by sophisticated approaches such as magnetic resonance imaging and ultrasonography. CTS symptoms can be ameliorated through conservative and surgical strategies. The exact CTS pathophysiology needs clarification. Genetic predispositions to CTS are augmented by various variants within genes; however, CTS etiology could include risk factors such as wrist movements, injury, and specific conditions (e.g., age, body mass index, sex, and cardiovascular conditions). The high prevalence of CTS diminishes the quality of life of its sufferers and imposes costs on health systems, hence the significance of research and clinical trials to elucidate CTS pathogenesis and develop novel therapeutic targets.

Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants.

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.

p.Gln318X and p.Val281Leu as the Major Variants of CYP21A2 Gene in Children with Idiopathic Premature Pubarche.

Premature pubarche (PP) is the appearance of sexual hair in children before puberty. The PP phenotype may attribute to nonclassic congenital adrenal hyperplasia (NC-CAH). In this study, we investigated the role of CYP21A2 gene variants in patients with PP in the Iranian population. Forty patients (13 males and 27 females), clinically diagnosed with PP, were analyzed for molecular testing of CYP21A2 gene variants. Direct sequencing was performed for the samples. Also, gene dosage analysis was performed for the cases. Fourteen patients (35%) had a mutation of p.Gln318X and p.Val281Leu, out of which 10% had regulatory variants. Approximately 10% of the patients were homozygous (NC-CAH). 78.5% (11/14) of patients had trimodular RCCX of which 5 patients had two copies of CYP21A1P pseudogene. The prevalence of p.Val281Leu was higher than p.Gln318X in PP patients. In conclusion, CYP21A2 variant detection has implications in the genetic diagnosis of PP phenotype. The genetic characterization of the CYP21A2 gene is important for characterizing the variable phenotype of carriers and genetic counseling of PP and NC-CAH patients.

Genetic homozygosity in a diverse population: An experience of long QT syndrome.

BACKGROUND: Genomic variations have shown an ethnic-specific pattern within various cohorts. Genetic variants of KCNQ1, KCNH2, SCN5A and KCNE1 causing LQT syndrome have been described in many populations. In this article the spectrum of variants of these genes is presented in Iranian patients. METHODS: 102 unrelated individuals diagnosed with LQT were enrolled in this study. Clinical and electrocardiogram (ECG) data of 95 patients were documented, and analyzed by expert pediatric cardiologists. Coding regions and exon-intron boundaries were amplified and sequenced. Segregation analysis was done for novel variants as well as in silico analyses. RESULTS: Sixty nine of 95 cases (73%) had Schwartz score of ≥3.5. The causal variants were found in 31 cases (9 novel variants). 21 patients had KCNQ1 (LQTS1) of which15 patients were homozygous for KCNQ1 variants, 9 of these patients (29%) had a Jervell and Lange-Nielsen phenotype. 4 patients had KCNH2 (LQTS2) variants, 7 cases had SCN5A had heterozygous variants, and 2 cases had heterozygous variants in KCNE1 (LQTS5). 19 variants were missense, 3 were nonsense, and 3 were frameshifts. There was one large deletion and 3 intronic variants. CONCLUSION: The yield of genetic testing and the genotype profile of LQTS patients in Iran is different from reports elsewhere, with lower overall yield and with 48% having homozygous states.

Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: A novel mutation and in silico analyses.

Brown-Vialetto-Van Laere syndrome, a rare neurological disorder is due to SLC52A3 mutations. Here, the SLC52A3 protein and its mutations are in silico structurally and functionally analyzed among all the reported patients and a novel mutation is also reported. After clinical evaluations, SLC52A3 gene was sequenced and segregation analysis of the mutations was also checked. A comprehensive search was performed on the reported mutations of SLC52A3 gene. In silico structural and functional analyses of the mutations and interactome analyses of the protein were done using available software tools. Mutations of 37 affected individuals were identified. Thirty three mutations were determined. c.502A > C was a novel variant that it was segregated within the family. One mutation (c.639C > G) was responsible for 12% of the mutations. Segregation analysis, secondary structure, functional prediction achieved for the novel mutation showed pathogenicity of this variant. BVVL is a very rare disorder; SLC52A3 mutations are distributed among different populations and there might be one frequent mutation in this gene. BVVL should be more considered in Iran. In addition to segregation analysis, computational analyses could accelerate understanding the extent of pathogenicity of the novel variants.

A novel PKP2 mutation and intrafamilial phenotypic variability in ARVC/D.

Background: Arrhythmogenic ventricular cardiomyopathy (AVC) is an inherited cardiac disorder affecting 1 in 1000 individuals worldwide. The mean diagnosed age of disease is 31 years. In this article, an Iranian family reported that they were affected by ARVC due to a novel PKP2 mutation. Methods: Clinical evaluations, 12-lead ECG, CMR, and signal-averaged ECG were performed. After DNA extraction, genetic testing was done, and PCR-sequencing was applied to find causal mutations. Segregation analysis was also performed for the family. Results: ARVC criteria were documented in the patients. Genetic testing revealed a novel chain termination mutation (p.Tyr168Ter) in PKP2 gene; this mutation was transmitted from the mother to her 23-year-old son, but only the son was affected with ARVC. Conclusion: Modifier genes were indicated using interactome analysis of Plakophilin 2 protein (PKP2); they might have led to phenotypic variability through cellular mechanisms, such as nonsense-mediated mRNA decay. At least, 9 proteins were identified that might have affected Plakophilin 2 protein function, and consequently, rationalizing this intrafamilial phenotypic variability. This study highlighted the role of modifier genes involved in ARVC as well as the major role of PKP2 mutation in developing the disease in our population.

Genotypic effect of a mutation of the MYBPC3 gene and two phenotypes with different patterns of inheritance.

BACKGROUND: MYBPC3 mutations have been described in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). A mutation, c.3373G>A, has been reported to cause autosomal recessive form of HCM. Here, we report that this mutation can cause autosomal dominant form of DCM. METHODS: Next-generation sequencing using targeted panel of a total of 23 candidate genes and following Sanger sequencing was applied to detect causal mutations of DCM. Computational analyses were also performed using available software tools. In silico structural and functional analyses including protein modeling and prediction were done for the mutated MYBPC3 protein. RESULTS AND CONCLUSION: Targeted sequencing showed one variant c.3373G>A (p.Val1125Met) in the studied family following autosomal dominant inheritance. Computational programs predicted a high score of pathogenicity. Secondary structure of the region surrounding p.Val1125 was changed to a shortened beta-strand based on prediction of I-TASSER and Phyre2 servers with high confidence value for the mutation. cMyBP-C protein was modeled to 3dmkA. Our findings suggest that one single mutation of MYBPC3 may have different effects on the cellular mechanisms based of its zygosity. Various factors might be considered for explaining this phenomenon. This gene may have an important role in Iranian DCM and HCM patients.

Autosomal Recessive Nonsyndromic Arrhythmogenic Right Ventricular Cardiomyopathy without Cutaneous Involvements: A Novel Mutation.

The arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic disease frequently associated with desmosomal mutations, mainly attributed to dominant mutations in the Plakophilin-2 (PKP2) gene. Naxos and Carvajal are the syndromic forms of ARVD/C due to recessive mutations. Herein, we report an autosomal recessive form of nonsyndromic ARVD/C caused by a mutation in the PKP2 gene. After examination and implementation of diagnostic modalities, the definite diagnosis of ARVD/C was confirmed by detection of ventricular tachycardia with a left bundle branch configuration and a superior axis, T-wave inversion in right precordial leads (i.e., V1-V3) in a 12-lead electrocardiogram, and a right ventricle outflow tract dilatation. Neither cutaneous involvement nor other abnormalities were observed. Genetic testing was performed during which an intronic mutation of c.2577+1G>T in the PKP2 gene was observed homozygously. The c.2577+1G>T disrupts PKP2 mRNA splicing and causes a nonsyndromic form of ARVD/C.

MYO15A splicing mutations in hearing loss: A review literature and report of a novel mutation.

Sensorineural hearing loss (SNHL) is the most prevalent genetic sensory defect in humans, affecting about 1 in 1000 newborns around the world. Non-syndromic SNHL accounts for nearly 70% of hereditary hearing loss and 80% of SNHL cases show an autosomal recessive mode of inheritance (ARNSHL). In the present study, we applied targeted-exome sequencing to a family with a single proband affected by congenital sensorineural hearing loss. 127 known genes were sequenced to find the causative mutation. One novel homozygous donor splice site mutation, c.4596 + 1G > A (IVS12 + 1G > A) was found in MYO15A gene. Analysis of this mutation within the family showed that the mutation segregates with hearing loss. New DNA sequencing technologies could lead to identification of the disease causing variants especially in highly heterogeneous disorders such as hearing loss.