Publications by authors named "Masoud Garshasbi"

96 Publications

Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family.

Mol Cell Pediatr 2021 May 9;8(1). Epub 2021 May 9.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: Ca as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation, and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1), which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene causes a very rare neuromuscular disease, myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca uptake. To date, 13 variants have been reported in MICU1 gene in 44 patients presented with the vast spectrum of symptoms.

Case Presentation: Here, we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH). We identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing (WES) and segregation analysis.

Conclusions: Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.
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http://dx.doi.org/10.1186/s40348-021-00116-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107061PMC
May 2021

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report.

BMC Neurol 2021 Apr 28;21(1):180. Epub 2021 Apr 28.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients.

Case Presentation: A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant-NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)-in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes.

Conclusions: Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the "RABopathies" term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.
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http://dx.doi.org/10.1186/s12883-021-02204-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080372PMC
April 2021

Crystallographic modeling of the PNPT1:c.1453A>G variant as a cause of mitochondrial dysfunction and autosomal recessive deafness; expanding the neuroimaging and clinical features.

Mitochondrion 2021 Apr 1;59:1-7. Epub 2021 Apr 1.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Deficiency of the proteins involved in oxidative phosphorylation (OXPHOS) can lead to mitochondrial dysfunction. Polyribonucleotide nucleotidyltransferase 1 (PNPT1) is one of the genes involved in the OXPHOS and encodes the mitochondrial polynucleotide phosphorylase (PNPase) which is implicated in RNA-processing exoribonuclease activity. Herein, we report a 34-month-old boy who presented with global developmental delay, muscular hypotonia, hearing impairment, and movement disorders including chorea and dystonia. Mitochondrial genome sequencing and whole-exome sequencing (WES) were performed and a variant in PNPT1:c.1453A>G; p. (Met485Val) was identified. A number of patient's neurologic problems had been already reported in previous studies, however, lower limbs spasticity and bulbar dysfunction were novel phenotypic findings. In addition, delayed myelination during infancy, progressive basal ganglia atrophy, and brain stem abnormal signals including transverse pontine fibers and superior colliculus involvement were also novel neuroimaging findings in this case. Different crystallographic modeling and stereochemical analysis of the c.1453A>G; p. (Met485Val) variant showed this variant affects the active site of the protein and disrupts the normal protein function.
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http://dx.doi.org/10.1016/j.mito.2021.03.012DOI Listing
April 2021

A novel deletion variant in CLN3 with highly variable expressivity is responsible for juvenile neuronal ceroid lipofuscinoses.

Acta Neurol Belg 2021 Mar 30. Epub 2021 Mar 30.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Mutations in CLN3 (OMIM: 607042) are associated with juvenile neuronal ceroid lipofuscinoses (JNCL)-a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration. The study aimed to determine the underlying genetic factors justifying the NCL phenotype in a large Iraqi consanguineous family. Four affected individuals with an initial diagnosis of NCL were recruited. By doing neuroimaging and also pertinent clinical examinations, e.g. fundus examination, due to heterogeneity of neurodevelopmental disorders, the proband was subjected to the paired-end whole-exome sequencing to identify underlying genetic factors. The candidate variant was also confirmed by Sanger sequencing. Various in silico predictions were used to show the pathogenicity of the variant. This study revealed a novel homozygous frameshift variant-NM_000086.2: c.1127del; p.(Leu376Argfs*15)-in the exon 14 of the CLN3 gene as the most likely disease-causing variant. Three out of 4 patients showed bilateral vision loss (< 7 years) and retinal degeneration with macular changes in both eyes. Electroencephalography demonstrated the loss of normal posterior alpha rhythm and also low amplitude multifocal slow waves. Brain magnetic resonance imaging of the patients with a high degree of deterioration showed mild cerebral and cerebellar cortical atrophy, mild ventriculomegaly, thinning of the corpus callosum and vermis, and non-specific periventricular white matter signal changes in the occipital area. The novel biallelic deletion variant of CLN3 was identified that most probably led to JNCL with variable expressivity of the phenotype. This study also expanded our understanding of the clinical and genetic spectrum of JNCL.
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http://dx.doi.org/10.1007/s13760-021-01655-9DOI Listing
March 2021

A novel missense variant in the LMNB2 gene causes progressive myoclonus epilepsy.

Acta Neurol Belg 2021 Mar 30. Epub 2021 Mar 30.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Progressive myoclonus epilepsies (PMEs) are a group of disorders embracing myoclonus, seizures, and neurological dysfunctions. Because of the genetic and clinical heterogeneity, a large proportion of PMEs cases have remained molecularly undiagnosed. The present study aimed to determine the underlying genetic factors that contribute to the PME phenotype in an Iranian female patient. We describe a consanguineous Iranian family with autosomal recessive PME that had remained undiagnosed despite extensive genetic and pathological tests. After performing neuroimaging and clinical examinations, due to heterogeneity of PMEs, the proband was subjected to paired-end whole-exome sequencing and the candidate variant was confirmed by Sanger sequencing. Various in-silico tools were also used to predict the pathogenicity of the variant. In this study, we identified a novel homozygous missense variant (NM_032737.4:c.472C > T; p.(Arg158Trp)) in the LMNB2 gene (OMIM: 150341) as the most likely disease-causing variant. Neuroimaging revealed a progressive significant generalized atrophy in the cerebral and cerebellum without significant white matter signal changes. Video-electroencephalography monitoring showed a generalized pattern of high-voltage sharp waves in addition to multifocal spikes and waves compatible with mixed type seizures and epileptic encephalopathic pattern. Herein, we introduce the second case of PME caused by a novel variant in the LMNB2 gene. This study also underscores the potentiality of next-generation sequencing in the genetic diagnosis of patients with neurologic diseases with an unknown cause.
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http://dx.doi.org/10.1007/s13760-021-01650-0DOI Listing
March 2021

Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum.

Hum Mutat 2021 May 14;42(5):491-497. Epub 2021 Mar 14.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

ATP8A2 is a P4-ATPase that flips phosphatidylserine across membranes to generate and maintain transmembrane phospholipid asymmetry. Loss-of-function variants cause severe neurodegenerative and developmental disorders. We have identified three ATP8A2 variants in unrelated Iranian families that cause intellectual disability, dystonia, below-average head circumference, mild optic atrophy, and developmental delay. Additionally, all the affected individuals displayed tooth abnormalities associated with defects in teeth development. Two variants (p.Asp825His and p.Met438Val) reside in critical functional domains of ATP8A2. These variants express at very low levels and lack ATPase activity. Inhibitor studies indicate that these variants are misfolded and degraded by the cellular proteasome. We conclude that Asp825, which coordinates with the Mg ion within the ATP binding site, and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also provide evidence on the association of tooth abnormalities with defects in ATP8A2, thereby expanding the clinical spectrum of the associated disease.
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http://dx.doi.org/10.1002/humu.24180DOI Listing
May 2021

The oncogenic and tumor suppressive roles of RNA-binding proteins in human cancers.

J Cell Physiol 2021 Feb 8. Epub 2021 Feb 8.

Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes  contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.
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http://dx.doi.org/10.1002/jcp.30311DOI Listing
February 2021

A novel metabolic disorder in the degradation pathway of endogenous methanol due to a mutation in the gene of alcohol dehydrogenase.

Clin Biochem 2021 Apr 2;90:66-72. Epub 2021 Feb 2.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: A small amount of methanol is produced endogenously in the human body but it is efficiently metabolized by alcohol dehydrogenase (ADH) and other enzymes, and the products eliminated without harm. In this study, we present a new entity of inborn error of methanol metabolism due to a mutation in the ADH1C gene coding for the γ subunit that is part of several ADH isoenzymes.

Results: This disorder was discovered in an 11.58-year-old boy. During one 9-month hospital admission, he had periods of 1-4 days during which he was comatose, and between these periods he was sometimes verbose and euphoric, and had ataxia, dysarthria. Following hemodialysis treatments, he became conscious and appeared healthy. Organ evaluations and his laboratory tests were normal. Toxicological evaluation of his blood showed a high methanol level [12.2 mg/dL (3.8 mmol/L), normal range up to 3.5 mg/dL (1.09 mmol/L) while the formaldehyde level was undetectable. The finding of liver function tests that were within normal limits, coupled with a normal eye examination and size of the liver, elevated blood methanol levels and an undetectable formaldehyde level, suggested ADH insufficiency. Adding zinc to the drug regimen 15 mg/daily dramatically reduced the patient's methanol level and alleviated the abnormal symptoms. When zinc supplementation was discontinued, the patient relapsed into a coma and hemodialysis was once again required. A homozygous mutation in ADH1C gene located at exon 3 was found, and both parents were heterozygous for this mutation.

Conclusion: Accumulation of methanol due to mutation in ADH1C gene may result in drunkenness and ataxia, and leads to coma. This condition can be successfully treated with zinc supplementation as the cofactor of ADH.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.01.007DOI Listing
April 2021

Identification of a Novel Splice Site Mutation in RUNX2 Gene in a Family with Rare Autosomal Dominant Cleidocranial Dysplasia.

Iran Biomed J 2020 Oct 19. Epub 2020 Oct 19.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: Pathogenic variants of RUNX2, a gene that encodes an osteoblast-specific transcription factor, have been shown as the cause of CCD, which is a rare hereditary skeletal and dental disorder with dominant mode of inheritance and a broad range of clinical variability. Due to the relative lack of clinical complications resulting in CCD, the medical diagnosis of this disorder is challenging, which leaves it underdiagnosed.

Methods: In this study, nine healthy and affected members of an Iranian family were investigated. PCR and sequencing of all exons and exon-intron boundaries of RUNX2 (NM_001024630) gene was performed on proband. Co-segregation analysis was conducted in the other family members for the identified variant. Additionally, a cohort of 100 Iranian ethnicity-matched healthy controls was screened by ARMS-PCR method.

Results: The novel splice site variant (c.860-2A>G), which was identified in the intron 6 of RUNX2 gene, co-segregated with the disease in the family, and it was absent in healthy controls. Pathogenicity of this variant was determined by several software, including HSF, which predicts the formation or disruption of splice donor sites, splice acceptor sites, exonic splicing silencer sites, and exonic splicing enhancer sites. In silico analysis predicted this novel variant to be disease causing.

Conclusion: The identified variant is predicted to have an effect on splicing, which leads to exon skipping and producing a truncated protein via introducing a premature stop codon.
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October 2020

Identification of a novel Mutation in an Iranian Family with suspected patient to GM2-gangliosidoses.

Clin Case Rep 2020 Dec 11;8(12):2583-2591. Epub 2020 Aug 11.

Department of Genetics Faculty of Basic Sciences Shahrekord University Shahrekord Iran.

Sandhoff disease is one of the GM2-gangliosidoses which is caused by a mutation in the preventing the breakdown of GM2-ganglioside. We report a novel variant in a family with a history of a dead girl with Sandhoff disease which was not found in controls.
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http://dx.doi.org/10.1002/ccr3.3103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752470PMC
December 2020

Identification of a novel RUNX2 gene mutation and early diagnosis of CCD in a cleidocranial dysplasia suspected Iranian family.

Clin Case Rep 2020 Dec 3;8(12):2333-2340. Epub 2020 Apr 3.

Medical Genetics Department DeNA Laboratory Tehran Iran.

This research resulted in the identification and submission of a novel RUNX2 gene mutation in the affected members of the studied pedigree. Mutation screening is an effective method for the early diagnosis of CCD in the affected individuals.
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http://dx.doi.org/10.1002/ccr3.2825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752336PMC
December 2020

Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss.

Mol Genet Genomic Med 2020 12 18;8(12):e1550. Epub 2020 Nov 18.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: Hereditary hearing loss (HL) is a heterogeneous and most common sensory neural disorder. At least, 76 genes have been reported in association with autosomal recessive nonsyndromic HL (ARNSHL). Herein, we subjected two patients with bilateral sensorineural HL in two distinct consanguineous Iranian families to figure out the underlying genetic factors.

Methods: Physical and sensorineural examinations were performed on the patients. Imaging also was applied to unveil any abnormalities in anatomical structures of the middle and inner ear. In order to decipher the possible genetic causes of the verified GJB2-negative samples, the probands were subjected to whole-exome sequencing and, subsequently, Sanger sequencing was applied for variant confirmation.

Results: Clinical examinations showed ARNSHL in the patients. After doing whole exome sequencing, two novel variants were identified that were co-segregating with HL that were absent in 100 ethnically matched controls. In the first family, a novel homozygous variant, NM_138691.2: c.530T>C; p.(lle177Thr), in TMC1 gene co-segregated with prelingual ARNSHL. In the second family, NM_022124.6: c.2334G>A; p.(Trp778*) was reported as a nonsense variant causing prelingual ARNSHL.

Conclusion: These findings can, in turn, endorse how TMC1 and CDH23 screening is critical to detecting HL in Iranian patients. Identifying TMC1 and CDH23 pathogenic variants doubtlessly help in the detailed genotypic characterization of HL.
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http://dx.doi.org/10.1002/mgg3.1550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767568PMC
December 2020

Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family.

Eur J Med Genet 2020 Dec 11;63(12):104096. Epub 2020 Nov 11.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Major facilitator superfamily domain-containing 2A (MFSD2A) is required for brain uptake of Docosahexaenoic acid and Lysophosphatidylcholine, both are essential for the normal neural development and function. Mutations in MFSD2A dysregulate the activity of this transporter in brain endothelial cells and can lead to microcephaly. In this study, we describe an 11-year-old male who is affected by autosomal recessive primary microcephaly 15. This patient also shows severe intellectual disability, recurrent respiratory and renal infections, low birth weight, and developmental delay. After doing clinical and neuroimaging evaluations, due to heterogeneity of neurogenetic disorders, no narrow clinical diagnosis was possible, therefore, we utilized targeted-exome sequencing to identify any causative genetic factors. This revealed a homozygous in-frame deletion (NM_001136493.1: c.241_243del; p.(Val81del)) in the MFSD2A gene as the most likely disease-susceptibility variant which was confirmed by Sanger sequencing. Neuroimaging revealed lateral ventricular asymmetry, corpus callosum hypoplasia, type B of cisterna magna, and widening of Sylvian fissures. All of these novel phenotypes are associated with autosomal recessive primary microcephaly-15 (MCPH15). According to the genotype-phenotype data, p.(Val81del) can be considered a likely pathogenic variant leading to non-lethal microcephaly. However, further cumulative data and molecular approaches are required to accurately identify genotype-phenotype correlations in MFSD2A.
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http://dx.doi.org/10.1016/j.ejmg.2020.104096DOI Listing
December 2020

Identification of a novel missense c.386G > A variant in a boy with the POMGNT1-related muscular dystrophy-dystroglycanopathy.

Acta Neurol Belg 2021 Feb 11;121(1):143-151. Epub 2020 Nov 11.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Muscular dystrophy-dystroglycanopathies are autosomal recessive neurologic disorders, caused by homozygous or compound heterozygous mutations in the POMGNT1 gene-encoding protein O-mannose beta-1,2-N-acetylglucosaminyl transferase. This type of muscular dystrophy is characterized by early-onset muscle weakness, gait ataxia, microcephaly, and developmental delay.We performed whole-exome sequencing to detect the disease-causing variants in a 4 year-old boy. Afterwards, Sanger sequencing was performed to confirm the detected variant in the patient and his family. We evaluated a 4 year-old Iranian boy presented with delayed speech and language development, gait ataxia, global developmental delay, motor delay, neurodevelopmental delay, postnatal microcephaly and strabismus. His parents were first cousins, and the mother had a history of spontaneous abortion. In this study, we report a novel missense c.386G > A; p.(Arg129Gln) variant in the POMGNT1 gene which was confirmed by Sanger sequencing in the patient and segregated with the disease in the family.
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http://dx.doi.org/10.1007/s13760-020-01527-8DOI Listing
February 2021

A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q.

Z Kinder Jugendpsychiatr Psychother 2020 Nov;48(6):478-489

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.

Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member. Cosegregation was confirmed by sequencing all available family members. Additionally, we analyzed 96 dyslexic individuals who had previously shown positive LOD scores on chromosome 4q28 as well as an even larger sample ( = 2591). We found a single prominent linkage interval on chromosome 4q, where sequence analysis revealed a nucleotide variant in the 3' UTR of brain expressed in the dyslexic family member that cosegregated with dyslexia. This sequence alteration might affect the binding efficiency of the IGF2BP1 RNA-binding protein and thus influence the expression level of the gene product. An analysis of 96 individuals from a cohort of dyslexic individuals revealed a second heterozygous variant in this gene, which was absent in the unaffected sister of the proband. An investigation of the region in a much larger sample further found a nominal -value of 0.0016 for verbal short-term memory (digit span) in 2,591 individuals for a neighboring SNV. After correcting for the local number of analyzed SNVs, and after taking into account linkage disequilibrium, we found this corresponds to a -value of 0.0678 for this phenotype. We describe a new locus for familial dyslexia and discuss the possibility that might play a role in the etiology of a monogenic form of dyslexia.
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http://dx.doi.org/10.1024/1422-4917/a000758DOI Listing
November 2020

Functional Analysis of S2486G Mutation and its Contribution to Pathogenesis of Ankylosing Spondylitis.

Arch Iran Med 2020 10 1;23(10):688-696. Epub 2020 Oct 1.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: Ankylosing spondylitis (AS; OMIM:106300) is a common complex inflammatory disease; in a previous study, we introduced a novel mutation in the gene (OMIM: 600514) which was associated with AS. This study is designed to investigate the potential effect of S2486G mutation on reelin secretion; additionally, we objected to evaluate the phospholipase A2 () gene (OMIM: 601690) expression and platelet-activating factor-acetylhydrolase (PAF-AH) concentration as the downstream gene and the encoded protein.

Methods: The impact of the S2486G on reelin protein secretion was investigated in CHO-K1 and HEK-293T cells by constructing wild-type and mutant plasmids. Besides, the possible effect of the mutation on expression and concentration of and PAF-AH in THP1 cells was assessed by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The study was performed at Tarbiat Modares University, Tehran, Iran, from 2016 to 2018.

Results: Our results showed that S2486G not only causes a significant reduction in reelin secretion in both HEK-293T and CHO-K1 cells, but also it leads to a significant reduction in gene expression ( value < 0.001) and protein level of PAF-AH in THP-1 cells ( value < 0.003).

Conclusion: The S2486G mutation in can alter inflammatory and, to some extent, osteogenesis pathways mediated by reduced secretion of reelin and also reduced expression of the gene.
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http://dx.doi.org/10.34172/aim.2020.87DOI Listing
October 2020

The identification of two pathogenic variants in a family with mild and severe forms of developmental delay.

J Hum Genet 2021 Apr 9;66(4):445-448. Epub 2020 Oct 9.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box, 14115-331, Tehran, Iran.

Intellectual disability (ID) accounts for 1% of the general population, and it is caused by the interplay between the genetic and/or environmental factors. The genetic components responsible for the development of ID are highly heterogeneous, and the phenotype and severity of the disease vary in patients even if they have an identical pathological variant and/or belong to the same family. Herein, we reported two male siblings with ID in an Iranian family. By means of the whole-exome sequencing method, elder brother affected by a moderate form of ID exhibited a de novo missense variant in the KCNQ3 gene, while another sibling afflicted with a severe form of the disease exhibited a de novo in-frame deletion in the UBE3A gene. Both variants have been previously ascribed to similar clinical phenotypes. In addition, a genetic variant in the KCNQ3 gene was transmitted to his son, who had a mild form of ID. To our knowledge, all individuals with KCNQ3-related developmental delay show de novo variants in the KCNQ3 gene. Thus, this familial case exhibit milder phenotype that might extend the clinical spectrum of KCNQ3 pathogenic variants. In addition, the current report highlights the significance of the clinical evaluation and non-biased assessment of the genetic analysis.
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http://dx.doi.org/10.1038/s10038-020-0809-8DOI Listing
April 2021

Distribution of the most common types of HPV in Iranian women with and without cervical cancer.

Women Health 2021 Jan 21;61(1):73-82. Epub 2020 Sep 21.

Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University , Tehran, Iran.

Cervical cancer is an important cause of death in women worldwide. About 99.7% of all cervical cancers have been related to human papillomavirus, especially types 16 and 18. Types 6 and 11 cause genital warts. We aimed to determine the prevalence of common HPV genotypes among women in the general population and women with cervical cancer. A total of 571 healthy women cytology specimens and 113 tissue samples of cervical cancer were investigated using HPV type-specific primers. HPV DNA was detected in 24% of healthy women: 3.3% were positive for high-risk HPV and 11.6% for low-risk HPV. HPV6 (9.3%) had the highest prevalence followed by HPV11 (2.3%), HPV16 (1.8%), HPV18 (1.2%), and 9.1% of samples were positive for unknown types. Among cervical cancer samples, HPV DNA was found in 78.8% including 43.4% HPV16, 8% HPV18, and 27.4% an unknown HPV type. HPV6 and HPV11 were not detected in any cervical cancer cases and 21.2% were negative for HPV. We found no association between HPV-16/18 and age in cervical cancer. The prevalence of HPV infection is relatively high in Iran without vaccination backgrounds. HPV DNA screening and vaccination programs can prevent cervical cancer and health problems caused by genital warts.
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http://dx.doi.org/10.1080/03630242.2020.1822490DOI Listing
January 2021

Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing.

J Clin Lab Anal 2020 Dec 30;34(12):e23544. Epub 2020 Aug 30.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Teheran, Iran.

Background: The extremely high genetic heterogeneity of hearing loss due to diverse group of genes encoding proteins required for development, function, and maintenance of the complex auditory system makes the genetic diagnosis of this disease challenging. Up to now, 121 different genes have been identified for nonsyndromic hearing loss (NSHL), of which 76 genes are responsible for the most common forms of NSHL, autosomal recessive nonsyndromic hearing loss (ARNSHL).

Methods: After excluding mutations in the most common ARNSHL gene, GJB2, by Sanger sequencing, genetic screening for a panel of genes responsible for hereditary hearing impairment performed in 9 individuals with ARNSHL from unrelated Iranian consanguineous pedigrees.

Results: One compound heterozygote and eight homozygote variants, of which five are novel, were identified: CDH23:p.(Glu1970Lys), and p.(Ala1072Asp), GIPC3:p.(Asn82Ser), and (p.Thr41Lys), MYO7A:p.[Phe456Phe]; p.[Met708Val], and p.(Gly163Arg), TECTA:p.(Leu17Leufs*19), OTOF:c.1392+1G>A, and TRIOBP:p.(Arg1068*). Sanger sequencing confirmed the segregation of the variants with the disease in each family.

Conclusion: Finding more variants and expanding the spectrum of hearing impairment mutations can increase the diagnostic value of molecular testing in the screening of patients and can improve counseling to minimize the risk of having affected children for at risk couples.
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http://dx.doi.org/10.1002/jcla.23544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755797PMC
December 2020

Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS.

Am J Med Genet A 2020 10 7;182(10):2391-2398. Epub 2020 Aug 7.

Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.

Al-Raqad syndrome (ARS) is a rare autosomal recessive congenital disorder, associated mainly with developmental delay, and intellectual disability. This syndrome is caused by mutations in DCPS, encoding scavenger mRNA decapping enzyme, which plays a role in the 3-prime-end mRNA decay pathway. Whole-exome sequencing was performed on an offspring of a consanguineous family presenting with developmental delay, intellectual disability, growth retardation, mild craniofacial abnormalities, cerebral and cerebellar atrophy, and white matter diffuse hypomyelination pattern. A novel biallelic missense variant, c.918G>C p. (Glu306Asp), in the DCPS gene was identified which was confirmed by sanger sequencing and segregation analysis subsequently. Few cases of ARS have been described up to now, and this study represents a 7-years-old boy presenting with central and peripheral nervous system impaired myelination in addition to ocular and dental manifestation, therefore outstretch both neuroimaging and clinical findings of this ultra-rare syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61776DOI Listing
October 2020

Novel imaging and clinical phenotypes of CONDSIAS disorder caused by a homozygous frameshift variant of ADPRHL2: a case report.

BMC Neurol 2020 Aug 3;20(1):291. Epub 2020 Aug 3.

Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.

Background: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive disorder caused by defects in the ADP-Ribosylhydrolase Like 2 (ADPRHL2; OMIM: 618170) gene. This gene encodes the ADP-ribosylhydrolase enzyme (ARH3) that eliminates the addition of poly-ADP ribose (PAR) in the cellular stress onto proteins in the ADP-ribosylation process in which adding one or more ADP-ribose moieties onto the target proteins in the post-translational modification have occurred. In this study, we report a new case of CONDSIAS in the Iranian population. A literature review of CONDSIAS is also included.

Case Presentation: A four-year-old female patient, born to a consanguineous Iranian family, was referred with various clinical symptoms including impaired speech, variable ataxia, infrequent seizures, and gradual onset of truncal hypotonia. Over time, she developed complete motor and speech regression, bilateral sensorineural hearing loss, infrequent seizures, abdominal distension and gastrointestinal (GI) intolerance, and loss of consciousness. To better molecularly diagnose, trio-whole-exome sequencing (WES) was performed on the proband and her parents. Sanger sequencing was also applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ADPRHL2 protein were predicted. All basic metabolic tests were normal, while serial coronal magnetic resonance imaging (MRI) showed progressive cerebral and cerebellar atrophy in addition to cerebral white matter signal changes as a novel neuroimaging finding. GI intolerance was another novelty of clinical scenarios in the patient. An auditory brainstem response test showed a severe bilateral sensorineural hearing loss. An electroencephalogram also confirmed focal seizures. From the molecular perspective, a novel homozygous frameshift variant in the ADPRHL2 gene (NM_017825.2; c.636_639del, p.(Leu212fs)) was identified by WES.

Conclusions: CONDSIAS is an ultra-rare neurodegenerative disorder. In the present study, we introduced extra-neurological and neuroimaging findings of this disorder in a female child caused by a novel frameshift variation in the ADPRHL2 gene.
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http://dx.doi.org/10.1186/s12883-020-01873-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397971PMC
August 2020

A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family.

Mol Genet Genomic Med 2020 10 22;8(10):e1413. Epub 2020 Jul 22.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: Homozygous loss-of-function mutations in TSEN54 (tRNA splicing endonuclease subunit 54; OMIM: 608755) cause different types of pontocerebellar hypoplasias (PCH) including PCH2, PCH4, and PCH5. The study aimed to determine the possible genetic factors contributing to PCH phenotypes in two affected male infants in an Iranian family.

Methods: We subjected two affected individuals in a consanguineous Iranian family. To systematically investigate the susceptible gene(s), whole-exome sequencing was performed on the proband and a novel identified variant was confirmed by Sanger sequencing. We also analyzed 26 relatives in three generations using PCR-restriction fragment length polymorphism (PCR-RFLP) followed and confirmed by Sanger sequencing.

Results: Physical and medical examinations confirmed PCH in the patients. Besides, the proband showed bilateral moderate sensorineural hearing loss and structural heart defects as the novel phenotypes. The molecular findings also verified that two affected individuals were homozygote for the novel synonymous variant, NM_207346.2: c.1170G>A; p.(Val390Val), in TSEN54. PCR-RFLP and Sanger sequencing elucidated that the parents and 16 relatives were heterozygote for the novel variant.

Conclusion: We identified a novel synonymous variant, c.1170G>A, in TSEN54 associated with PCH in an Iranian family. Based on this study, we strongly suggest using "TSENopathies" to show the overlapped phenotypes among different types of PCH resulted from TSEN causative mutations.
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http://dx.doi.org/10.1002/mgg3.1413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549571PMC
October 2020

A novel variant of ST3GAL3 causes non-syndromic autosomal recessive intellectual disability in Iranian patients.

J Gene Med 2020 11 3;22(11):e3253. Epub 2020 Aug 3.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Background: The number of reported genes causing non-syndromic autosomal recessive intellectual disability (NS-ARID) is increasing. For example, mutations in the ST3GAL3 gene have been reported to be associated with NS-ARID. In the present study, we aimed to determine the genetic cause of the NS-ARID in a five-generation consanguineous Iranian family.

Methods: We subjected four patients with an initial diagnosis of NS-ID in an Iranian family. To identify the possible genetic cause(s), whole-exome sequencing was performed on the proband and Sanger sequencing was applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ST3Gal-III were predicted.

Results: The common clinical features were detected in all affected members who were suffering from a severe ID. Using whole-exome sequencing, a novel variant, c.704C>T or p.(Thr235Met), in exon 9 of the ST3GAL3 gene (NM_001270461.2, OMIM# 606494) was identified and verified by Sanger sequencing. This variant is located next to the VS motif of ST3Gal-III, which is a vital part of the catalytical domains.

Conclusions: In the present study, we identified a novel missense variant, c.704C>T or p.(Thr235Met), in the ST3GAL3. To our knowledge, is the third variant in this gene to be associated with NS-ARID. Our findings highlight the need for further investigations into the mechanisms by which variants in ST3GAL3 contribute to neurological dysfunction.
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http://dx.doi.org/10.1002/jgm.3253DOI Listing
November 2020

Identification of novel loss of function variants in MBOAT7 resulting in intellectual disability.

Genomics 2020 11 6;112(6):4072-4077. Epub 2020 Jul 6.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

The membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene codes for an enzyme involved in regulating arachidonic acid incorporation in lysophosphatidylinositol. Patients with homozygous nonsense mutations in MBOAT7 have intellectual disability (ID) accompanied with seizure and autism. Accumulating evidences obtained from human genetic studies have shown that MBOAT7 is also involved in fatty liver disease. Here we identified two novel homozygous variants in MBOAT7, NM_024298.5: c.1062C>A; p.(Tyr354*) and c.1135del; p.(Leu379Trpfs*9), in two unrelated Iranian families by means of whole exome sequencing. Sanger sequencing was performed to confirm the identified variants and also to investigate whether they co-segregate with the patients' phenotypes. To understand the functional consequences of these changes, we overexpressed recombinant wild type MBOAT7 and mutants in vitro and showed these mutations resulted in abolished protein synthesis and expression, indicating a complete loss of function. Albeit, we did not trace any liver diseases in our patients, but presence of globus pallidus signal changes in Magnetic Resonance Images might be indicative of metabolic changes as a result of loss of MBOAT7 expression in hepatic cells. These signal changes could also help as an important marker of MBOAT7 deficiency while analyzing the genomic data of patients with similar phenotypes.
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http://dx.doi.org/10.1016/j.ygeno.2020.07.008DOI Listing
November 2020

The Identification and Stereochemistry Analysis of a Novel Mutation p.(D367Tfs*61) in the CYP1B1 Gene: A Case Report.

J Curr Ophthalmol 2020 Jan-Mar;32(1):114-118. Epub 2020 Mar 23.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Purpose: To investigate the presence of a probable genetic defect(s) that may cause primary congenital glaucoma (PCG) in a seven-year-old female patient.

Methods: A seven-year-old female patient and her family received genetic counseling and underwent full clinical examinations by an expert ophthalmologist. The patient's genomic DNA was subjected to the targeted gene capture and next-generation sequencing (NGS) along with Sanger sequencing method. The 3D structure prediction and stereochemistry analysis were performed for both mutant and wild-type forms of the CYP1B1 protein.

Results: The clinical examinations indicated that the diagnosis of PCG was correctly made. We identified a novel homozygous deletion in which a "C" nucleotide was deleted from the final exon of the Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) gene. The 3D molecular modeling of the CYP1B1 protein predicted significant structural changes could occur in this protein as a result of the mutation mentioned earlier. The stereochemistry analysis revealed mutant features of the protein, as well as significant misfolding and possible malfunctions in the mutant form of the CYP1B1 protein.

Conclusions: This mutation might cause a frameshift in the translation process, leading to the malfunction of the CYP1B1 protein and development of glaucoma. This newly-identified mutation could be regarded as potential deletion mutation in genetic counseling and molecular examination for the detection of PCG disease in Iran.
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http://dx.doi.org/10.1016/j.joco.2019.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265266PMC
March 2020

Three Novel Variants identified in FBN1 and TGFBR2 in seven Iranian families with suspected Marfan syndrome.

Mol Genet Genomic Med 2020 08 19;8(8):e1274. Epub 2020 May 19.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Teheran, Iran.

Background: Marfan syndrome (MFS) is a multi-systemic autosomal dominant disease of the connective tissue characterized by the early development of thoracic aneurysms/dissections, along with various manifestations of the ocular and skeletal systems. Due to the genetic and clinical heterogeneity, the clinical diagnosis of this disorder is challenging. Loss-of-function mutations in FBN1 (encodes fibrillin-1) lead to MFS type 1. Also, similar mutations in transforming growth factor β receptor 2 (TGFBR2) gene cause MFS type 2. Both proteins involve in TGF-β signaling.

Methods: In this study, genetic screening using a panel involving 14 genes, especially FBN1 and TGFBR2, were performed on seven representatives affected members of seven unrelated Iranian families suspected with MFS. To confirm the variants, Sanger sequencing was applied to other affected/unaffected members of the families.

Results: A total of 13 patients showed MFS manifestations. Using genetic screening, two novel and three previously reported variants in FBN1 were identified. We also detected two variants (a novel and a previously reported variant) in the TGFBR2 gene.

Conclusion: In this study, we introduce three novel variants identified through gene screening in seven Iranian MFS families. This report is expected to considerably improve genetic counseling for Iranian MFS families. Early precise molecular diagnosis can be helpful for better management and improving the life expectancy of these patients.
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http://dx.doi.org/10.1002/mgg3.1274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434737PMC
August 2020

Homozygous in-frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family.

Ann Hum Genet 2020 07 20;84(4):315-323. Epub 2020 Feb 20.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

The human dopamine transporter (hDAT) participates in dopamine homeostasis by clearing dopamine from the extracellular space using secondary active transport. Dysregulation of hDAT has been reported to be associated with different neuropsychiatric disorders. Dopamine transporter deficiency syndrome (DTDS) is a complex disease caused by defects in dopamine uptake within the synaptic cleft and patients manifest parkinsonian features. The extracellular loops are crucial for DAT activity and defects in these regions disturb dopamine transport. In the present study, a 3.5-year-old female in a consanguineous Iranian family with an initial diagnosis of gait imbalance and speech delay has been identified. We utilized whole-exome sequencing (WES) to identify the possible genetic defect(s). WES identified a novel homozygous in-frame indel variant, c.1139_1150del; p.(Gly380_Lys384delinsGlu), in the SLC6A3 gene (NM_001044.4), as the most likely disease-susceptibility variant. This variant is located in extracellular loop 4 (EL4) of the DAT protein. Our study highlights the role of extracellular loops and shows the EL4 of hDAT as a critical region for the protein activity. The identified variant in the EL4 region of DAT is predicted to compromise DAT function and may lead to DTDS in this case. However, complementary studies are required to confirm.
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http://dx.doi.org/10.1111/ahg.12378DOI Listing
July 2020

Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8.

Eur J Med Genet 2020 May 28;63(5):103868. Epub 2020 Jan 28.

Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Pathogenic variants in NKX6-2 gene causing autosomal recessive spastic ataxia type 8 with hypomyelinating leukodystrophy have been reported in few families around the world. In this study, we performed Whole Exome Sequencing and identified a novel missense variant, c.501C > G; p.(Phe167Leu), in two affected siblings with main manifestations of global developmental delay, motor regression, hypotonia, clonus in lower limbs and muscle bulk atrophy especially in the upper limbs, spasticity and contracture, scoliosis, hip dislocation, oculomotor apraxia, horizontal and vertical nystagmus. In addition, wrist and foot drop due to peripheral axonal neuropathy were observed in these patients as a new clinical finding and cerebellar white matter involvement in brain Magnetic Resonance Imaging (MRI) as new imaging finding. Therefore, we expanded the manifestations of NKX6-2-related disorders in this manuscript.
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http://dx.doi.org/10.1016/j.ejmg.2020.103868DOI Listing
May 2020

Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS.

Eur J Hum Genet 2020 06 30;28(6):754-762. Epub 2020 Jan 30.

Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Ankylosing spondylitis (AS) is a common complex inflammatory disease; however, up to now distinct genes with monogenic pattern have not been reported for this disease. In the present study, we report a large Iranian family with several affected members with AS. DNAs of the three affected and two healthy cases were chosen for performing whole-exome sequencing (WES). After several filtering steps, candidate variants in the following genes were detected: RELN, DNMT1, TAF4β, MUC16, DLG2, and FAM208. However, segregation analysis confirmed the association of only one variant, c.7456A>G; p.(Ser2486Gly) in the RELN gene with AS in this family. In addition, in silico predictions supported the probable pathogenicity of this variant. In this study, for the first time, we report a novel variant in the RELN gene, c.7456A>G; p.(Ser2486Gly), which completely co-segregates with AS. This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies.
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http://dx.doi.org/10.1038/s41431-020-0573-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253431PMC
June 2020

A novel missense variant in GPT2 causes non-syndromic autosomal recessive intellectual disability in a consanguineous Iranian family.

Eur J Med Genet 2020 May 21;63(5):103853. Epub 2020 Jan 21.

Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Intellectual disability (ID) affects 1-3% of the general population worldwide. Genetic factors play an undeniable role in the etiology of Non-Syndromic Intellectual disability (NS-ID). Nowadays, whole-exome sequencing (WES) technique is used frequently to identify the causative genes in such heterogeneous diseases. Herein, we subjected four patients with initial diagnostics of NS-ID in a consanguineous Iranian family. To find the possible genetic cause(s), Trio-WES was performed on the proband and his both healthy parents. Sanger sequencing was performed to confirm the identified variant by WES and also investigate whether it co-segregates with the patients' phenotype in the family. Using several online in-silico predictors, the probable impacts of the variant on structure and function of GPT2 protein were predicted. A novel variant, c.266A>G; p.(Glu89Gly), in exon 3 of GPT2 (NM_133443.3) was identified using Trio-WES. The candidate variant was also verified by Sanger sequencing. All affected members showed the common clinical features suffering from a non-progressive mild-to-severe ID. Also, different clinical observations compared to previously reported cases such as no facial features, no obvious structural malformations, ability to speak but with difficulty, and lack of any morphological defects were noted for the first time in this family. The c.266A>G; p.(Glu89Gly) variant reported here is the sixth variant identified up to now in the GPT2 gene, to be associated with NS-ID. Our data support the potential malfunction of the substituted GPT2 protein resulted from the novel variant, however, we strongly suggest confirming this finding more by doing functional analysis.
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http://dx.doi.org/10.1016/j.ejmg.2020.103853DOI Listing
May 2020