Introduction: TPP1 variants have been identified as a causative agent of neuronal ceroid lipofusc... more Introduction: TPP1 variants have been identified as a causative agent of neuronal ceroid lipofuscinosis 2 disease, that ataxia is one of its clinical features. Therefore, here, molecular study of TPP1 variants is presented in an Iranian cohort and a novel pathogenic variant is described. Methods: This investigation was conducted as a cross-sectional study in a tertiary referral hospital, Children’s Medical Center, Pediatrics Center of Excellence. Clinical presentations and pedigrees were documented. Patients with cerebellar ataxia were enrolled in this study. Next-generation sequencing was applied to confirm the diagnosis. Segregation and bioinformatics analyses were also done for the variants using Sanger sequencing. Results: Forty-five patients were included in our study. The mean age of onset was 104 (+55.60) months (minimum = 31 months, maximum = 216 months). The majority of cases (73.3%) were born to consanguineous parents and only 1 patient (2.2%) had an affected sibling. Of t...
Context: Pathogenic variants in SLC26A4 gene are the third-most frequent cause of autosomal reces... more Context: Pathogenic variants in SLC26A4 gene are the third-most frequent cause of autosomal recessive hearing loss in different populations. Aims: This article reports results of homozygosity mapping and SLC26A4 variant analysis in Iran. Settings and Design: A case series study was performed on forty GJB2-negative Iranian deaf families. Subjects and Methods: Homozygosity mapping, using microsatellite markers flanking the SLC26A4 gene, was performed on GJB2-negative Iranian deaf families. The SLC26A4 variant analysis was done by Sanger sequencing. A literature review was performed to identify all reported SLC26A4 pathogenic variants in Iran. Results: In one of the families, the hearing loss showed co-segregation with the DFNB4 STR markers. A previously reported SLC26A4 pathogenic variant was identified in homozygous state in all the affected members of this family. The literature review showed that variant screening of only three SLC26A4 exons and their boundary regions can detect variants responsible for deafness in about half of all DFNB4 Iranian deaf cases. Conclusions: The results of this study emphasize the important role of SLC26A4 pathogenic variants in the development of deafness in Iran. More information on the frequency of pathogenic variants can help in choosing faster and cost-effective methods for genetic testing.
Hearing loss is a serious sensory defect in the world. Mutations in the GJB2 and GJB6 genes are t... more Hearing loss is a serious sensory defect in the world. Mutations in the GJB2 and GJB6 genes are the major causes of autosomal recessive nonsyndromic hearing loss (NSHL). Recently, three major large deletions in the GJB6 gene including del(GJB6-D13S1830), del(GJB6-D13S1854), and a > 920 kb deletion have been reported to form double heterozygosity with GJB2. This may suggest that deletions involving GJB6 may be responsible for some NSHL. We designed a real time SYBR green-based PCR to quantify a common deleted region in GJB6 gene. The amplified region covers the area which has been seen to be deleted in all of the above reports. We selected nine families heterozygous for different mutations in GJB2 gene to investigate the presence of deletions in the GJB6 gene. The samples were run along with controls for normal hearing and heterozygous and homozygous for GJB2 mutations to optimize our method. As a reference gene or external standard, a segment of the CLCN7 gene was also quantified as well. We did not detect any deletion in the GJB6 gene. Using this method, any deletion involving GJB6 gene can be detected in a rapid and sensitive way.
BackgroundGiant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that... more BackgroundGiant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease‐causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families.MethodsClinical and imaging data of patients were recorded and evaluated, retrospectively. Whole‐exome sequencing (WES) was undertaken in order to detect disease‐causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013–2...
Abstract Genetic diagnoses especially using single-gene and/or NGS tests are available for inheri... more Abstract Genetic diagnoses especially using single-gene and/or NGS tests are available for inherited cardiovascular diseases. NGS technologies have revolutionized our understanding of the molecular mechanisms of cardiovascular disorders, which provides insights on potential therapies. Cascade screening is recommended when a pathogenic variant is identified in a patient. In the genetic evaluation of a child with a congenital heart defect (CHD), it is a critical step to determine if it is syndromic or isolated CHD. Approximately 30%–50% and 80% of DCM and HCM patients, respectively, have a genetic etiology. Genetic testing in patients with arrhythmias and cardiomyopathies is usually used for confirmation of diagnosis as well as risk for stratification and patient management.
OBJECTIVES Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; i... more OBJECTIVES Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; infantile AxD is the most common severe form which usually results in death. In this study, phenotype and genotype analysis of all reported cases with IAxD are reported as well as a de novo variant. METHODS We conduct a comprehensive review on all reported Infantile AxD due to GFAP mutation. Clinical data and genetics of the reported patients were analyzed. Clinical evaluations, pedigree drawing, MRI and sequencing of GFAP were performed. RESULTS 135 patients clinically diagnosed with IAxD had GFAP mutations. A total of fifty three variants of GFAP were determined; 19 of them were located at 1A domain. The four common prevalent variants (c 0.715C>T, c 0.236G˃A, c 0.716G˃A, and c 0.235C˃T) were responsible for 64/135 (47.4%) of the patients. Seizure was the dominant clinical symptom (62.3%) followed by macrocephaly (41%), developmental delay (23.9%) and spasticity (23.9%). A de novo variant c 0.715C˃T was found in the presented Iranian case. DISCUSSION The majority of GFAP variant are located in a specific domain of the protein. Seizure as the most common symptom of IAxD could be considered. This study highlighted the role of genetic testing for diagnosing AxD.
international cardiovascular research journal, 2020
: Background: Congenital Heart Disease (CHD) is a major health problem around the world. Several ... more : Background: Congenital Heart Disease (CHD) is a major health problem around the world. Several maternal and fetal risk factors have been mentioned to be associated with development of CHD. However, the epidemiological pattern is different in various parts of the world. Thus, the present study aimed to demonstrate the descriptive characteristics of a group of Iranian children with CHD. Objectives: The present study aimed to determine the regional distribution of CHD among 1000 Iranian hospitalized children during three years. Methods: This cross-sectional study was conducted on 1000 Iranian children with CHD who were hospitalized in Rajaie Cardiovascular, Medical and Research Center, as a tertiary cardiovascular hospital (2017 - 2019). The participants were selected via convenience sampling. Clinical data were extracted from the patients’ medical records and questionnaires and then, a comprehensive evaluation was performed. Results: The median (IQR) age of the children was 18 (8 - 60) months. In addition, the mean ± SD of maternal age at pregnancy was 27.3 ± 5.92 years. Ventricular Septal Defect (VSD) was the most frequent CHD. Most of the patients were Fars (35.7%), Azeri (18.4%), and Kurd (10.7%). Besides, 58.7% of the patients lived in rural areas. The family history of CHD was present in 23.9% of the patients. Additionally, 41.4% of the patients’ parents had consanguineous marriages. Spotting was the most common (48.7%) complication during pregnancy followed by infectious disease (24.2%), toothache (12.9%), and diabetes mellitus (7.8%). Conclusions: The present study demonstrated the baseline neonatal and maternal characteristics of the patients with CHD, which revealed that some risk factors were common in these individuals. Hence, it is necessary to provide preventive strategies for modifiable risk factors, monitor high-risk pregnant women at shorter intervals, raise awareness in the general population, and perform genetic counselling, as appropriated. This was the first report of the CHD frequency in Iran.
Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. G... more Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. Genetic variations are among the identifiable primary causes of these syndromes. However, some patients have been reported to be affected by EOEE without any other clinical symptoms and signs. We study the genotype and phenotype of patients with nonsyndromic early-onset epileptic encephalopathy (NSEOEE) and report 2 novel patients from Iran. A comprehensive search was conducted in PubMed, John Willy, Springer, Elsevier, and Google Scholar databases to collect related information of all the previously reported cases with KCTD7 mutations. Fifty-four patients (from 40 families) were investigated. Using trio-whole-exome sequencing (trio-WES) and Sanger sequencing, the possible genetic causes of the disorder were checked. The probable impacts of the identified variants on the KCTD7 protein structure and function were predicted. This study provided a detailed overview of all published KCTD7 mut...
Familial glucocorticoid deficiency is a rare autosomal recessive genetic disorder which belongs t... more Familial glucocorticoid deficiency is a rare autosomal recessive genetic disorder which belongs to a group of primary adrenal insufficiency (PAI) and is mainly caused by mutations in the MC2R and MRAP genes. A comprehensive search was conducted to find the reported variants of MC2R and MRAP genes. In silico pathogenic analysis was performed for the reported variants. PCR amplification and sequencing were performed for three patients. Structural analysis, modeling, and interactome analysis were applied to characterize novel MC2R variants and their proteins. About 80% of MC2R-related cases showed the clinical symptoms which were diagnosed at <2 years old. 107 patients had MC2R mutations (85 homozygotes, 21 compound heterozygotes, and 1 simple heterozygote). 59 variants were found in the MC2R gene. Four mutations were responsible for half of patients. 39 homozygous patients had MRAP mutations; 14 variants were determined in the MRAP gene. Nine proteins were predicted by STRING to as...
Introduction: TPP1 variants have been identified as a causative agent of neuronal ceroid lipofusc... more Introduction: TPP1 variants have been identified as a causative agent of neuronal ceroid lipofuscinosis 2 disease, that ataxia is one of its clinical features. Therefore, here, molecular study of TPP1 variants is presented in an Iranian cohort and a novel pathogenic variant is described. Methods: This investigation was conducted as a cross-sectional study in a tertiary referral hospital, Children’s Medical Center, Pediatrics Center of Excellence. Clinical presentations and pedigrees were documented. Patients with cerebellar ataxia were enrolled in this study. Next-generation sequencing was applied to confirm the diagnosis. Segregation and bioinformatics analyses were also done for the variants using Sanger sequencing. Results: Forty-five patients were included in our study. The mean age of onset was 104 (+55.60) months (minimum = 31 months, maximum = 216 months). The majority of cases (73.3%) were born to consanguineous parents and only 1 patient (2.2%) had an affected sibling. Of t...
Context: Pathogenic variants in SLC26A4 gene are the third-most frequent cause of autosomal reces... more Context: Pathogenic variants in SLC26A4 gene are the third-most frequent cause of autosomal recessive hearing loss in different populations. Aims: This article reports results of homozygosity mapping and SLC26A4 variant analysis in Iran. Settings and Design: A case series study was performed on forty GJB2-negative Iranian deaf families. Subjects and Methods: Homozygosity mapping, using microsatellite markers flanking the SLC26A4 gene, was performed on GJB2-negative Iranian deaf families. The SLC26A4 variant analysis was done by Sanger sequencing. A literature review was performed to identify all reported SLC26A4 pathogenic variants in Iran. Results: In one of the families, the hearing loss showed co-segregation with the DFNB4 STR markers. A previously reported SLC26A4 pathogenic variant was identified in homozygous state in all the affected members of this family. The literature review showed that variant screening of only three SLC26A4 exons and their boundary regions can detect variants responsible for deafness in about half of all DFNB4 Iranian deaf cases. Conclusions: The results of this study emphasize the important role of SLC26A4 pathogenic variants in the development of deafness in Iran. More information on the frequency of pathogenic variants can help in choosing faster and cost-effective methods for genetic testing.
Hearing loss is a serious sensory defect in the world. Mutations in the GJB2 and GJB6 genes are t... more Hearing loss is a serious sensory defect in the world. Mutations in the GJB2 and GJB6 genes are the major causes of autosomal recessive nonsyndromic hearing loss (NSHL). Recently, three major large deletions in the GJB6 gene including del(GJB6-D13S1830), del(GJB6-D13S1854), and a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 920 kb deletion have been reported to form double heterozygosity with GJB2. This may suggest that deletions involving GJB6 may be responsible for some NSHL. We designed a real time SYBR green-based PCR to quantify a common deleted region in GJB6 gene. The amplified region covers the area which has been seen to be deleted in all of the above reports. We selected nine families heterozygous for different mutations in GJB2 gene to investigate the presence of deletions in the GJB6 gene. The samples were run along with controls for normal hearing and heterozygous and homozygous for GJB2 mutations to optimize our method. As a reference gene or external standard, a segment of the CLCN7 gene was also quantified as well. We did not detect any deletion in the GJB6 gene. Using this method, any deletion involving GJB6 gene can be detected in a rapid and sensitive way.
BackgroundGiant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that... more BackgroundGiant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease‐causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families.MethodsClinical and imaging data of patients were recorded and evaluated, retrospectively. Whole‐exome sequencing (WES) was undertaken in order to detect disease‐causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013–2...
Abstract Genetic diagnoses especially using single-gene and/or NGS tests are available for inheri... more Abstract Genetic diagnoses especially using single-gene and/or NGS tests are available for inherited cardiovascular diseases. NGS technologies have revolutionized our understanding of the molecular mechanisms of cardiovascular disorders, which provides insights on potential therapies. Cascade screening is recommended when a pathogenic variant is identified in a patient. In the genetic evaluation of a child with a congenital heart defect (CHD), it is a critical step to determine if it is syndromic or isolated CHD. Approximately 30%–50% and 80% of DCM and HCM patients, respectively, have a genetic etiology. Genetic testing in patients with arrhythmias and cardiomyopathies is usually used for confirmation of diagnosis as well as risk for stratification and patient management.
OBJECTIVES Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; i... more OBJECTIVES Alexander disease (AxD) is a rare autosomal dominant disorder due to GFAP mutations; infantile AxD is the most common severe form which usually results in death. In this study, phenotype and genotype analysis of all reported cases with IAxD are reported as well as a de novo variant. METHODS We conduct a comprehensive review on all reported Infantile AxD due to GFAP mutation. Clinical data and genetics of the reported patients were analyzed. Clinical evaluations, pedigree drawing, MRI and sequencing of GFAP were performed. RESULTS 135 patients clinically diagnosed with IAxD had GFAP mutations. A total of fifty three variants of GFAP were determined; 19 of them were located at 1A domain. The four common prevalent variants (c 0.715C>T, c 0.236G˃A, c 0.716G˃A, and c 0.235C˃T) were responsible for 64/135 (47.4%) of the patients. Seizure was the dominant clinical symptom (62.3%) followed by macrocephaly (41%), developmental delay (23.9%) and spasticity (23.9%). A de novo variant c 0.715C˃T was found in the presented Iranian case. DISCUSSION The majority of GFAP variant are located in a specific domain of the protein. Seizure as the most common symptom of IAxD could be considered. This study highlighted the role of genetic testing for diagnosing AxD.
international cardiovascular research journal, 2020
: Background: Congenital Heart Disease (CHD) is a major health problem around the world. Several ... more : Background: Congenital Heart Disease (CHD) is a major health problem around the world. Several maternal and fetal risk factors have been mentioned to be associated with development of CHD. However, the epidemiological pattern is different in various parts of the world. Thus, the present study aimed to demonstrate the descriptive characteristics of a group of Iranian children with CHD. Objectives: The present study aimed to determine the regional distribution of CHD among 1000 Iranian hospitalized children during three years. Methods: This cross-sectional study was conducted on 1000 Iranian children with CHD who were hospitalized in Rajaie Cardiovascular, Medical and Research Center, as a tertiary cardiovascular hospital (2017 - 2019). The participants were selected via convenience sampling. Clinical data were extracted from the patients’ medical records and questionnaires and then, a comprehensive evaluation was performed. Results: The median (IQR) age of the children was 18 (8 - 60) months. In addition, the mean ± SD of maternal age at pregnancy was 27.3 ± 5.92 years. Ventricular Septal Defect (VSD) was the most frequent CHD. Most of the patients were Fars (35.7%), Azeri (18.4%), and Kurd (10.7%). Besides, 58.7% of the patients lived in rural areas. The family history of CHD was present in 23.9% of the patients. Additionally, 41.4% of the patients’ parents had consanguineous marriages. Spotting was the most common (48.7%) complication during pregnancy followed by infectious disease (24.2%), toothache (12.9%), and diabetes mellitus (7.8%). Conclusions: The present study demonstrated the baseline neonatal and maternal characteristics of the patients with CHD, which revealed that some risk factors were common in these individuals. Hence, it is necessary to provide preventive strategies for modifiable risk factors, monitor high-risk pregnant women at shorter intervals, raise awareness in the general population, and perform genetic counselling, as appropriated. This was the first report of the CHD frequency in Iran.
Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. G... more Early-onset epileptic encephalopathies (EOEE) affect cognitive, sensory, and motor development. Genetic variations are among the identifiable primary causes of these syndromes. However, some patients have been reported to be affected by EOEE without any other clinical symptoms and signs. We study the genotype and phenotype of patients with nonsyndromic early-onset epileptic encephalopathy (NSEOEE) and report 2 novel patients from Iran. A comprehensive search was conducted in PubMed, John Willy, Springer, Elsevier, and Google Scholar databases to collect related information of all the previously reported cases with KCTD7 mutations. Fifty-four patients (from 40 families) were investigated. Using trio-whole-exome sequencing (trio-WES) and Sanger sequencing, the possible genetic causes of the disorder were checked. The probable impacts of the identified variants on the KCTD7 protein structure and function were predicted. This study provided a detailed overview of all published KCTD7 mut...
Familial glucocorticoid deficiency is a rare autosomal recessive genetic disorder which belongs t... more Familial glucocorticoid deficiency is a rare autosomal recessive genetic disorder which belongs to a group of primary adrenal insufficiency (PAI) and is mainly caused by mutations in the MC2R and MRAP genes. A comprehensive search was conducted to find the reported variants of MC2R and MRAP genes. In silico pathogenic analysis was performed for the reported variants. PCR amplification and sequencing were performed for three patients. Structural analysis, modeling, and interactome analysis were applied to characterize novel MC2R variants and their proteins. About 80% of MC2R-related cases showed the clinical symptoms which were diagnosed at <2 years old. 107 patients had MC2R mutations (85 homozygotes, 21 compound heterozygotes, and 1 simple heterozygote). 59 variants were found in the MC2R gene. Four mutations were responsible for half of patients. 39 homozygous patients had MRAP mutations; 14 variants were determined in the MRAP gene. Nine proteins were predicted by STRING to as...
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