Ehsan Ghayoor Karimiani

Inherited peripheral neuropathies (IPNs) represent a clinically and genetically heterogeneous group of disorders affecting sensory, motor, autonomic functions, and can also present as a part of complex neurogenetic syndromes. Charcot-Marie-Tooth disease (CMT) is the most prevalent type of IPN. Despite advances in genetic testing, the diagnostic process remains challenging due to genetic heterogeneity and overlapping clinical phenotypes. We performed a comprehensive genetic evaluation of 126 patients presenting with symptoms of IPN. Nineteen patients with a typical CMT phenotype were initially screened for PMP22 copy number variations using Multiplex Ligation-dependent Probe Amplification (MLPA). Whole-exome sequencing (WES) was subsequently performed in 107 patients. Of these, 72 (63.7%) were classified as pathogenic or likely pathogenic, including 36 novel variants (50.0%), yielding an overall WES diagnostic rate of 62.6% (67/107). CMT-spectrum disorders identified by MLPA (n = 19 patients) and WES (n = 33 patients) accounted for 41.3% (52/126) of the study cohort. Additional diagnoses included hereditary sensory neuropathy 3.97% (5/126), distal hereditary motor neuropathy 4.76% (6/126), spastic paraplegia 3.97% (5/126), spinocerebellar ataxia 5.56% (7/126), spastic ataxia 8.73% (11/126), mitochondrial disease 7.94% (10/126), and other complex neurogenetic disorders 23.81% (30/126). Our findings highlight the utility of genomic sequencing approaches for resolving clinically heterogeneous neuropathy presentations and demonstrate the value of WES in a highly consanguineous Iranian cohort. These results support the role of WES in advancing precision medicine approaches for inherited neuropathies.

Epilepsy is a diverse and often severe neurological disorder characterized by frequent and unpredictable seizures caused by the simultaneous discharge of brain cells in one or both hemispheres. Recently, there has been a significant shift in the approach to healthcare, moving from a standardized model to a more personalized and targeted model. This transformation has been made possible by advances in pharmacogenomics. It has great potential in customizing treatments based on the specific needs of patients, and this is particularly evident in the management of epilepsy. With ongoing research, the development of comprehensive genetic databases, and the integration of pharmacogenomics into clinical practice using artificial intelligence, a brighter future can be expected for personalized epilepsy treatment. Using the potential of pharmacogenomics, we can expect to provide the best possible care for epilepsy patients and improve their quality of life.

Peroxisome biogenesis disorders (PBDs) are a genetically heterogeneous group of metabolic diseases caused by impaired peroxisome assembly and function. PBDs exhibit striking clinical variability, ranging from lethal neonatal forms (e.g., Zellweger spectrum disorders) to milder childhood-onset presentations such as rhizomelic chondrodysplasia punctata. While elevated levels of very-long-chain fatty acids (VLCFAs) remain a key diagnostic feature, the existence of unusual cases with normal plasma VLCFA levels highlight the limitations of relying solely on this biochemical marker for diagnosis. Genetic variations in PEX6, an important peroxisome biogenesis factor, contribute significantly to this phenotypic diversity, with missense variants often associated with less severe disease compared to truncating mutations. Recent studies further implicate dysregulated pexophagy—a targeted autophagic degradation of peroxisomes—in the underlying disease mechanisms. This review underscores the necessity for a multifaceted diagnostic approach that, thorough clinical assessment, detailed biochemical evaluation, and advanced molecular genetic testing, seeks to improve diagnostic accuracy and patient care, particularly in pediatric populations. Advancements in identifying novel biomarkers and targeted therapies offer promise for tailored interventions, underscoring the importance of precision medicine in optimizing outcomes for pediatric PBD patients.

Background: Plectinopathy-associated disorders are caused by mutations in the PLECTIN (PLEC) gene encoding Plectin protein. PLEC mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation. Methods: A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020 _2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of PLEC candidate variants. Results: We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for PLEC. Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy. Conclusion: We report plectinopathy-associated disorders to expand clinical phenotypes in different types of PLEC-related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disorder caused by a mutation in the MEFV gene and characterized by recurrent episodes of fever and polyserositis. Objectives: This study aimed to identify the frequency and distribution of MEFV mutations in children with FMF in northeastern Iran and determine clinical examinations. Methods: Our study was a descriptive and analytical cross-sectional study conducted among 29 patients under the age of 18 who visited the pediatric rheumatologist between April 2014 and 2021. After clinical diagnosis, the patients underwent genetic evaluation. The mutations related to each patient were identified using Sanger sequencing of the entire MEFV gene sequence. The rest of the information was extracted from the checklist. Finally, the data were analyzed using SPSS v. 16. Results: Fever was the most common symptom, followed by abdominal pain. During the acute attack period, laboratory inflammatory factors increased in all patients. None of the patients had complications. There was no significant relationship between the demographic variables in the groups (benign, variant of uncertain significance [VUS], pathogen) except for the rate of hospitalization (P-value = 0.039). Moreover, 34.5% of the studied patients had pathogenic mutations. The most common mutation was E148Q, which was reported to be benign, followed by pathogenic mutations (M680I), with a frequency of 10.2%. Conclusions: The FMF is rare in Northeastern Iran, and the number of pathogenic mutations is lower compared to Northwest Iran and other studies. It is necessary to conduct a genetic examination and treatment of affected patients to control the course of the disease and its complications.

Background: ECEL1 has been presented as a causal gene of an autosomal recessive form distal arthrogryposis (DA) which affects the distal joints. The present study focused on bioinformatic analysis of a novel mutation in ECEL1, c.535A>G (p. Lys179Glu), which was reported in a family with 2 affected boys and fetus through prenatal diagnosis.Methods: Whole‐exome sequencing data analyzed followed by molecular dynamic (MD) simulation of native ECEL1 protein and mutant structures using GROMACS software. One variant c.535A>G, p. Lys179Glu (homozygous) on gene ECEL1 has been detected in proband which was validated in all family members through Sanger sequencing.Results: We demonstrated remarkable constructional differences by MD simulation between wild‐type and novel mutant of ECEL1 gene. The reason for the lack of the Zn ion binding in mutation in the ECEL1 protein has been identified by average atomic distance and SMD analysis among the wild‐type and mutant.Conclusion: Overall, in this study, we present knowledge of the effect of the studied variant on the ECEL1 protein leading to neurodegenerative disorder in humans. This work may hopefully be supplementary to classical molecular dynamics to dissolve the mutational effects of cofactor‐dependent protein.

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.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co‐activator complex activity, similarly to what was observed in Menke‐Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5‐binding region. Recently, TTC5‐related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5‐related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre‐ and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Background The relationship between thrombophilia genes and recurrent pregnancy loss has been discussed. The aim of this study was to investigate the association between of MTHFR C677T, A1298C, F2G20210A, and F5 G1691A genetic variants among Iranian women with recurrent miscarriage. Methods A total of 245 women with two or more recurrent pregnancy loss, with mean age years were enrolled in the study. To compare genotypes, we have selected 250 healthy women without history of miscarriage as control group. Genomic DNA of participants was evaluated using polymerase chain reaction followed by Sanger sequencing to determine the genotype frequency. Results The mean age were 32.16 ± (21–42) and 31.81 ± (19–40) for case and control groups respectively. MTHFR C677T and A1298C mutant alleles were found to be significantly more prevalent in patients than control. However, F2G20210A and F5 G1691A genetic variants showed no significance. Conclusion The allele frequencies for the assessed genotypes in this study are consistent with the data obtained for other countries. We observed significant susceptible effects of MTHFR C677T, and A1298C among participants. According to the relatively high prevalence of these variants, we recommend genetic testing for women with RPL before therapeutic decisions.