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Abstract Copy number variations in the SMN1 gene on chromosome 5 are the primary cause of Spinal Muscular Atrophy (SMA) disease, characterized by muscle weakness and degeneration due to impaired alpha motor neurons in the spinal cord. To obtain a comprehensive molecular understanding of the SMA, including carriers, silent carriers, and patients in the Iranian population, we analyzed data from 5224 individuals referred to Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran, between 2006 and 2023 using MLPA and quantitative RT-PCR methods. The carrier frequency of SMA was estimated to be 5.55%. Furthermore, 3.06% of SMA parents (n = 24) had two copies of the SMN1 gene. Among 725 patients, those with an earlier onset of SMA were more likely to have two copies of the SMN2 gene (46.45%) and no copies of the NAIP gene (49.36%). Among the 654 fetal samples screened for SMA, 22.33% were found to be affected, while 3.46% of their parents tested normal. These findings are valuable for genetic counseling, carrier screening, and prenatal diagnosis of SMA in Iran. Furthermore, they underscore the importance of CNV analysis of SMN1, SMN2, and NAIP genes for accurate diagnosis and prognosis of SMA.

Abstract Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype–phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

Abstract Background Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacial anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III. Methods We performed RNA sequencing on blood samples to obtain insights into the biological pathways influenced by POLR3B mutation. We applied the results of our RNA-Seq analysis to several gene ontology programs such as ToppGene, Enrichr, KEGG. Results A significant decrease in expression of several spliceosomal RNAs, ribosomal proteins, and transcription factors was detected in the affected, compared to unaffected, family members. Conclusions We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes, and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2 and GATA1 contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of the spliceosome and ribosomal proteins in intellectual disability.

Abstract Background To date, over 400 syndromes with hearing impairment have been identified which altogether constitute almost 30% of hereditary hearing loss (HL) cases around the globe. Manifested as complete or partial labyrinthine aplasia (severe malformations of the inner ear structure), type I microtia (smaller outer ear with shortened auricles), and microdontia (small and widely spaced teeth), labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome (OMIM 610706) is an extremely rare autosomal recessive condition caused by bi‐allelic mutations in the FGF3 gene. Methods Using the whole‐exome sequencing (WES) data of the proband, we analyzed a consanguineous Iranian family with three affected members presenting with congenital bilateral HL, type I microtia, and microdontia. Results We discovered the homozygous deletion c.45delC in the first exon of the FGF3 gene, overlapping a 38.72 Mb homozygosity region in chromosome 11. Further investigations using Sanger sequencing revealed that this variant co‐segregated with the phenotype observed in the family. Conclusion Here, we report the first identified case of LAMM syndrome in Iran, and by identifying a frameshift variant in the first exon of the FGF3 gene, our result will help better clarify the phenotype–genotype relation of LAMM syndrome.

POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.

Abstract Background Guanine nucleotide exchange factors (GEFs) play pivotal roles in neuronal cell functions by exchanging GDP to GTP nucleotide and activation of GTPases. We aimed to determine the genotype and phenotype spectrum of GEF mutations by collecting data from a large Iranian cohort with intellectual disability (ID) and/or developmental delay (DD). Methods We collected data from nine families with 20 patients extracted from Iranian cohort of 640 families with ID and/or DD. Next‐generation sequencing (NGS) was used to identify the causing variants in recruited families. We also compared our clinical and molecular findings with previously reported patients carrying mutations in these GEF genes in the literature published until mid‐2021. Results We identified disease‐causing variants in eight GEF genes including ALS2, IQSEC2, MADD, RAB3GAP1, RAB3GAP2, TRIO, ITSN1, and DENND2A. The major clinical manifestations in 203 previously reported cases along with our 20 patients with disease causing variants in eight GEF genes were as follow; speech disorder (85.2%), ID (81.6%), DD (81.1%), inability to walk (71.3%), facial dysmorphisms features (52.4%), abnormalities in skull morphology (55.6%), hypotonia and muscle weakness (47%), and brain MRI abnormalities (43.4%). Conclusion Our study provides new insights into the genotype and phenotype spectrum of mutations in GEF genes.

Summary: Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) is part of the four-part ASC-1 transcriptional cointegrator complex. This complex includes ASCC1 (associated with spinal muscular atrophy with congenital bone fractures 2), TRIP4 (associated with spinal muscular atrophy with congenital bone fractures 1), and ASCC2 (not yet associated with human disease.) ASCC3 encodes a DNA helicase responsible for generating single-stranded DNA as part of the DNA damage response. Interestingly, ASCC3 expresses coding and non-coding isoforms, which act in opposition to balance the recovery of gene transcription after UV-induced DNA damage. Here we report the discovery of ASCC3 as the cause of a neuromuscular syndrome in seven unreported individuals from six unrelated families and updates on the one previously reported family. All the individuals share a neurologic phenotype that ranges from severe developmental delay to muscle fatigue. There appears to be genotype-phenotype correlation, as the most mildly affected individual is homozygous for a rare missense variant, while the more severely affected individuals are compound heterozygotes for a missense and a presumed loss-of-function (LOF) variant. There are no individuals with biallelic presumed LOF variants in our cohort or in gnomAD, as this genotype may not be compatible with life. In summary we report a syndrome in these eleven individuals from seven families with biallelic variants in ASCC3.

Abstract Background The X chromosome has historically been one of the most thoroughly investigated chromosomes regarding intellectual disability (ID), whose etiology is attributed to many factors including copy number variations (CNVs). Duplications of the long arm of the X chromosome have been reported in patients with ID, short stature, facial anomalies, and in many cases hypoplastic genitalia and/or behavioral abnormalities. Methods Here, we report on a large Iranian family with X‐linked ID caused by a duplication on the X chromosome identified by whole genome sequencing in combination with linkage analysis. Results Seven affected males in different branches of the family presented with ID, short stature, seizures, facial anomalies, behavioral abnormalities (aggressiveness, self‐injury, anxiety, impaired social interactions, and shyness), speech impairment, and micropenis. The duplication of the region Xq13.2q13.3, which is ~1.8 Mb in size, includes seven protein‐coding OMIM genes. Three of these genes, namely SLC16A2, RLIM, and NEXMIF, if impaired, can lead to syndromes presenting with ID. Of note, this duplicated region was located within a linkage interval with a LOD score >3. Conclusion Our report indicates that CNVs should be considered in multi‐affected families where no candidate gene defect has been identified in sequencing data analysis.

Abstract Defects of CIB2, calcium‐ and integrin‐binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type‐IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2−/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2−/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair‐cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2−/− mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture.

Objectives: Hearing loss (HL) is the most common sensory disorder, and affects 1 in 1000 newborns. About 50% of HL is due to genetics and 70% of them are non-syndromic with a recessive pattern of inheritance. Up to now, more than 50 genes have been detected which are responsible for autosomal recessive non-syndromic hearing loss, (ARNSHL). In Iran, HL is one of the most common disabilities due to consanguineous marriages. The aim was to investigate the prevalence of three new ARHL genes (GJB4, GJC3, and SLITRK6) reported in neighboring countries among Iranian families with ARNSHL. Methods: One hundred unrelated families with at least two affected siblings in consanguineous marriage, who were negative for GJB2 gene mutations, were selected. By using three STR markers for each gene, homozygosity mapping was performed. Results: Two families showed linkage to GJB4, six families were linked to GJC3 and only one family linked to SLITRK6. The samples of these families who showed linkage were sent for Sanger sequencing to detect the causative mutations. However, after analyzing the sequencing results, no mutation could be detected in either of the families. Molecular analysis for these nine families is underway in order to determine the pathogenic mutations using whole exome sequencing. Discussion: These data demonstrate a very low prevalence of mutation in these three genes (GJB4, GJC3, and SLITRK6) in the Iranian population, since no mutation was detected in our study group of 100 families.

Objective: Intellectual Disability (ID) characterize by significant limitations both in intellectual functioning and in adaptative behavior, originates before the age of 18. Over 70% of severe to profound intellectual disabilities (ID) caused by genetic factors. The aim of this study was to investigate genetic causes of ID in fourty Ahvazi families and provide information for genetic counseling, carrier detection, and prenatal diagnosis. Materials & Methods: In collaboration with Welfare Organization of Khuzestan Province, a total of 183 ID families from Ahwaz were investigated from which 40 (62 male and 42 female) families whose ID had been confirmed by psychiatrist and had more than one affected individual were selected for molecular analysis. Blood samples were collected from all normal and affected individuals in each family on EDTA pre-coated tubes. Thorough clinical characterization, dysmorphism examinations, karyotype analysis were carried out for all of the patients. Results: Three out of 40 (7.5%) families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed none of families had metabolic disorder. None of three families with primary microcephaly showed linkage to any of the seven known MCPH loci. Conclusion: The most common causes of ID in Ahvaz was Fragile X syndrome and Autosomal Reccesive Primary Microcephaly with the frequency of (7.5%). It seems that autosomal reccesive primary microcephaly is a relatively common heterogenous condition in Ahvaz.

Objective:Several studies have implicated the 5-HTTLPR polymorphism in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness in Iranian patients suffering from major depressive disorder (MDD).Methods:The sample consisted of 104 patients, with Fars ethnic background, who were diagnosed according to DSM-IV-TR criteria. Beck Depression inventory was used to evaluate the severity of the symptoms during the follow-up, and to determine clinical response of the patients at 4th and 8th week, respectively.Results:Our results showed a correlation between the genotype and response to antidepressant drug citalopram, (odds ratios for L/S and L/L were 3.90 (95 percent CI: 1.29- 11.80) and 1.90 (95 percent CI: 0.72-5.08), respectively).Conclusion:In conclusion, our results reveal that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes in Iranian patients after citalopram treatment.

Objective: About 50% of severe to profound intellectual disabilities (ID) are caused by genetic factors. In this study we decided to investigate the genetic causes of ID in 69 Bushehrian families to provide information for genetic counseling, carrier detection, and prenatal diagnosis. Materials & Methods: In this study we excluded known chromosomal abnormalities. The majority of families had more than two affected individuals. Karyotyping for each proband with physical malformations was performed. One affected member from each family was tested for FMR1 mutation and metabolic screening. Families with ID and primary microcephaly were checked for 7 known MCPH genes by linkage analysis. Results: Chromosomal abnormality was not found in any of the families. One family had full mutation of CGG repeat of Fragile-X syndrome. Six out of 18 families with MCPH showed linkage to one of the MCPH loci. One family had a syndrome associated with microcephaly. Two families with microcephaly and one family with a non-syndromic form of mental retardation without microcephaly showed an autosomal dominant mode of inheritance. Conclusion: According to our results genetic causes of ID are very heterogeneous and autosomal recessive primary microcephaly has an extremely high prevalence (26.09%) in Bushehr province of Iran.

Here we report a stop-mutation in the BOD1 (Biorientation Defective 1) gene, which co-segregates with intellectual disability in a large consanguineous family, where individuals that are homozygous for the mutation have no detectable BOD1 mRNA or protein. The BOD1 protein is required for proper chromosome segregation, regulating phosphorylation of PLK1 substrates by modulating Protein Phosphatase 2A (PP2A) activity during mitosis. We report that fibroblast cell lines derived from homozygous BOD1 mutation carriers show aberrant localisation of the cell cycle kinase PLK1 and its phosphatase PP2A at mitotic kinetochores. However, in contrast to the mitotic arrest observed in BOD1-siRNA treated HeLa cells, patient-derived cells progressed through mitosis with no apparent segregation defects but at an accelerated rate compared to controls. The relatively normal cell cycle progression observed in cultured cells is in line with the absence of gross structural brain abnormalities in the affected individuals. Moreover, we found that in normal adult brain tissues BOD1 expression is maintained at considerable levels, in contrast to PLK1 expression, and provide evidence for synaptic localization of Bod1 in murine neurons. These observations suggest that BOD1 plays a cell cycle-independent role in the nervous system. To address this possibility, we established two Drosophila models, where neuron-specific knockdown of BOD1 caused pronounced learning deficits and significant abnormalities in synapse morphology. Together our results reveal novel postmitotic functions of BOD1 as well as pathogenic mechanisms that strongly support a causative role of BOD1 deficiency in the aetiology of intellectual disability. Moreover, by demonstrating its requirement for cognitive function in humans and Drosophila we provide evidence for a conserved role of BOD1 in the development and maintenance of cognitive features.

Objective: The aim of this study was to investigate the genetic causes of autosomal recessive intellectual disabilities (AR-ID) in Hamadan province of Iran. Materials & Methods: In this descriptive-analytical cross-sectional study, 25 families with more than one affected with putative autosomal recessive intellectual disability were chosen with collaboration of Welfare Organization of Hamadan province. Families were included a total of 60 patients (39 male and 21 female) whose intellectual disability had been confirmed by Raven IQ test. Each family was asked for clinical examination and getting consent form. Blood sample was collected from each family. One proband from each family was tested for CGG repeat expansion in FMR1 gene, chromosomal abnormalities and inborn errors of metabolism. We also performed homozygosity mapping based on STR markers for seven known MCPH loci in families with primary microcephaly and AR-ID. Results: Five families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed one family with Medium Chain Acyl CoA Dehydrogenase deficiency. None of three families with primary microcephaly and AR-ID showed linkage to any of known seven MCPH loci. Conclusion: The main causes of ID in Hamadan province were Fragile X syndrome and Autosomal Recessive Primary Microcephaly with the frequencies of 20% and 12%, respectively.

Objective: About 70 percent of mental retardation can be attributed to genetic causes. Whereas the recognization of genetic causes of mental retardation causes better programming and more precision council for prevention and control of mental retardation, so the aim of this study is to investigate the genetic causes of mental retardation in Golestan province. Materials & Methods: In this descriptive research which is a cross-sectional and applied study, fifty families with two or more affected children from different parts of Golestan province were collected with cooperation of Golestan state welfare organization and by simple sampling method. Mental retardation of affected people had been previously proved by physicians. Blood samples of patients and controls in the family were prepared. Patients were investigated for dysmorphism and microcephaly. Cytogenetic study, metabolic test, fragile X test, and linkage analysis for seven gene loci known for autosomal recessive primary microcephaly (MCPH) was carried out. Results: Chromosomal abnormalities were not observed in any family. One out of fifty families revealed fragile X syndrome and ten were affected to MCPH. Five out of ten microcephaly families were linked to MCPH (autosomal recessive primary microcephaly) loci. Conclusion: Autosomal recessive primary microcephaly (MCPH)make up about 20% 0f all mental retardation in Golestan province. This prevalence is very remarkable.

Objectives: Myotonic Dystrophy type I (DM1) is a dominantly inherited disorder with a multisystemic pattern affecting skeletal muscle, heart, eye, endocrine and central nervous system. DM1 is associated with the expansion and instability of CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene located on chromosome 19q13.3. The aim of this study was to determine clinical and genetic characteristic of DM1 in Iranian patients. Genotype-phenotype correlation was also assessed in a small group of studied patients. Methods: Twenty six DM1 patients belonging to seventeen families were analyzed. Clinical assessment was based on the muscular disability rating scale (MDRS) and a sum of symptoms score (SSS). Molecular analysis (PCR and Southern blot) was used to clarify uncertain clinical diagnosis and in order to confirm clinical findings. Results: There was an inverse and significant correlation between age of onset and expanded allele length (P=0.026, tau-b=-0.360) based on Kendall's tau-b correlation coefficient, while there was no significant correlation between age of onset and severity of the clinical symptoms (P

Objective: Hereditary hearing loss (HHL) is a very common disorder. When inherited in an autosomal recessive manner, it typically presents as an isolated finding. Interestingly and unexpectedly, in spite of extreme heterogeneity, mutations in one gene, GJB2, are the most common cause of congenital severe-to-profound deafness in many different populations. In this study, we assessed the contributions made by GJB2 mutations and deletion in a portion of GJB6 to the autosomal recessive non-syndromic deafness genetic load in Iran. Materials & Methods: In this descriptive and cross – sectional study1605 probands from 1605 different nuclear families with autosomal recessive non-syndromic hearing loss were investigated. Hearing loss tests and clinical examination were done and 10 ml blood was drawn as DNA source. After study of 35delG mutation by ARMs PCR, negative or heterozygote individuals were sent to IOWA University for detection of other GJB2 mutations. Results: GJB2-related deafness was found in 243 families (15.1%). Conclusion: Varient geographic pattern for GJB2-related deafness has considerable results in Iran in comparable with other study in Europe and our neighboring countries and deletion in GJB6. [∆ (GJB6-D13S1830)] hasn't been detected in our studied population.

Objective: Congenital hearing loss occurs in 1 out of 1000 births and about 50% of all cases are estimated to be of genetic origin. About 70% of hereditary hearing loss is non-syndromic with autosomal recessive inheritance accounting for 80% of the genetic load. To assess the importance of other loci in the Iranian population, we screened 50 consanguineous families with ARNSHL for DFNB21, which was linked to ARNSHL in Middle East countries. Materials & Methods: 50 consanguineous families with at least three affected children, previously excluded by mutational analysis from GJB2 and GJB6 genes, were included in this study. We used three polymorphic markers including D11S1998, D11S4464, and D11S1299 in this study. Results: Two families were linked to DFNB21 and two novel mutations have been detected so far. In two families a 266 Del T mutation and a large 9611bp deletion that starts from intron 9 and includes exon 10 in TECTA gene were detected. Conclusion: This study showed that mutations in DFNB21 locus are the most common cause of ARNSHL in Iranian population. It seems that DFNB21 may play an important role in genetic load of ARNSHL in Iran. This will be confirmed by screening more families for this locus in Iranian deaf population.

Objective: Neuromuscular disordres are a gorup of heterogenous inherited diseases. More than 150 types of these group of disorders have been known.The criticals that were used for classification of these disease include: age of onset, clinical course, disease progression and type of inheritance. Neuromuscular disorders have been classified in four categories: Myopaties (Muscular dystrophies) Neuropathy (Charcot-Marie-Tooth dieseas), Motor neuron junction (Myasthenia Syndrome) Motor neuron disorder (Spinal muscular atrophy). Objective of this study was classification of neuromuscular disorders based on clinical criteria, molecular and immunohistochemical analysis that reffered to Genetic Research Center. As a result of neuromuscular disorders was the second most common disabilities, more investigation in this group of disorders is necessary in Iranian population so this study was performed for the first time in Iranian patients. Materials & Methods: Total of 143 patient with neuromuscular deficiency that clinical, EMG and muscle enzymes have been tested and also in some cases molecular and immunohistochemical analysis was performed. Results: 82 patients with myotonic dystrophy, 19 patients with DMD/BMD, 6 patients with congenital muscular dystrophy, 3 patients with FSHD, 10 patients with SMA, 2 patients with CMS and 21 patients with LGMD. For the other cases we need more molecular and definite clinical analysis. Conclusion: For some cases that DM1 was not confirmed, study of DM2 is recommended. In patients with LGMD that analysis with 5 Abs were normal we advised multiple western blot for them (including calpain, sarcoglycans, dysferlin). Study of congenital muscular dystrophy besides merosin analysis, investigation for the other involved protein and molecular testing for mutation detection is considrable.

It has been estimated that approximately one in 1000 live births suffer from profound deafness, and greater than 50% of this group is genetic etiology. So far more than 300 different genetic conditions responsible for deafness have been reported that among them 70% are non-syndromic and the rest are syndromic. Non-syndromic and syndromic hearing loss may be divided into Autosomal dominant (DFNA), Autosomal recessive (DFNB), X-linked (DFN), and mitochondrial. Approximately 75-80% are autosomal recessive, 10-20% autosomal dominant, 1-5% X-linked, and 0-2% mitochondrial. To date, 51 DFNA loci, 61 DFNB loci, and 7 DFN loci have been described. Non-syndromic hearing loss is divided into two postlingual and perlingual groups. As a general rule, most autosomal dominant non-syndromic hereditary hearing impaired is postlingual, while autosomal recessive non-syndromic hereditary hearing impaired is prelingual.

The incidence of profound congenital hearing loss is about 1 in 1,000 live birth. There are more than 50 distinct genetic loci (known as DFNB loci) at which mutations can cause recessive hearing loss. DFNB4, one recessive locus for deafness, also maps to 7q31 considerably for nonsyndromic hearing loss and Pendred Syndrome which has been named PDS gene. Pendred syndrome (PS, MIM 274600) with an estimated frequency 1-8 per 100,000, is an autosomal recessive disorder and classically characterized by sensor neural hearing loss and goiter. Here, we reported a family with Pendred syndrome that in which a new mutation, T420I, in the homozygous state caused the condition. Also there was a 9-year-old boy in the related family with hearing loss and with no signs of thyroid dysfunction or goiter, whom was compound heterozygous for PDS mutations including 1197delT and T420I. Both of these mutations result to PDS syndrome. However we are not sure if the 9-year old boy show the goiter appearance in near future, but the results could be used as the prognostic factor. Consequently we should follow up the patient. Besides all, characterization of mutations in PDS gene can guide us to early diagnosis of Pendred syndrome and consequently early treatment of the patients maybe show the clinical features of hypothyroidism in later onset.

Objective: Hereditary Hearing loss (HHL) affects one in 1000-2000 newborns and more than 50% of these cases, the loss has a genetic basis. About 70% of HHL is non-syndromic with autosomal recessive forms accounting for ~85% of the genetic load. To date, more than 100 locus estimated for this kind of deafness. Different genes have been reported to be involved, but mutations in the connexin 26 gene (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss. The aim of this project is to study the prevalence of connexin 26 mutations. Materials & Methods: In this descriptive study, the prevalence of connexin 26 mutations was evaluated by using amplification refractory mutation system (ARMS)-PCR for detection of 35delG and then analyzed all samples excluding 35delG homozygote by DHPLC and direct sequencing. 38 patients with autosomal recessive non-syndromic hearing loss were selected simply and participated in this research. Results: 76 chromosomes (38 patient) were screened for GJB2 mutations. Thirty two (42%) carry GJB2 mutations including 35 delG, W24X, R32H, R127H, -3170G>A. Among them, 35 delG has the highest frequency (84%). Polymorphism V153I was found in three chromosomes. Conclusion: According to these results, other loci and genes may be the major responsible for nonsyndromic deafness in this population.

Hereditary Hearing loss (HHL) affects one in 2000 netborns and more than 50% of these cases, the loss has a genetic basis. About 70% of HHL is non-syndromic with autosomal recessive mode of inheritance accounting for ~85% of the genetic load and more than hundred loci have been estimated for this kind of deafness. A 4–year-old boy and her sixteen-year- old sister, both suffering from congenital deafness without any other clinical symptoms were referred to Genetics Research Center to be screened for molecular basis of their phenotype. Bases on clinical observation, autosomal recessive non-syndromic hearing loss was dignosed for both of them. Using linkage analysis their phenotype localized to 6p21-3 chromosome in which COL11A2 has been located Several mutations have been reported in this gene associated with stickler syndrome type3 and non-syndromic hearing loss, both with autosomal dominant form of inheritance. In this study linkage between COL11A2 gene in DFNA13 locus, causative for autosomal dominant hearing loss, and phenotype of autosomal recessive non-syndromic hearing loss in and Iranian family was analyzed and Pro621Thr mutation was found in this family. Pro 621 Thr mutation found in this study is the first report of COL11A2 mutation associatied with autosomal recessive non-syndromic hearing loss.

Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1-3% of the world's population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.

Coronary artery disease (CAD) is the leading cause of mortality in many parts of the world. Genome-wide association studies (GWAS) have identified several genetic variants associated with CAD in Low-density lipoprotein receptor (LDLR) locus. This study was evaluated the possible association of genetic markers at LDLR locus with CAD irrespective to lipid profile and as well as the association of these SNPs with severity of CAD in Iranian population. Sequencing of 2 exons in LDLR gene (Exon 2, 12) and part of intron 30 of SMARCA4 gene include rs1122608, was performed in 170 Iranian patients angiographically confirmed CAD and 104 healthy controls by direct sequencing. Sullivan's scoring system was used for determining the severity of CAD in cases. Our results showed that homozygote genotypes of rs1122608 (P

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.

Objective: Hearing impairment is the most frequent sensorineural defect in 2 forms, syndromic and non–syndromic. The aim of this study is haplotype analysis of seven loci of non–syndromic autosomal recessive hearing loss in Iranian families. Materials & Methods: In this descriptive study, forty one Iranian families with 2 or more affected individuals segregating as an autosomal recessive non–syndromic hearing loss were selected simply and conveniently. The patients have been tested negative for the following loci, DFNB1, DFNB2, DFNB3, DFNB4, DFNB6, DFNB7/11, DFNB8/10, DFNB9, DFNB12, DFNB16, DFNB18, DFNB21, DFNB23, DFNB29 and DFNB4 previously. The subjects have been investigated additional 7 loci (DFNB22, DFNB28, DFNB30, DFNB31, DFNB36, DFNB37 and DFNB67) , to determine the prevalence of these genes involve in these loci. Homozygosity mapping was applied using number of STR (Short Tandem Repeat) markers. Results: Three families linked to the following loci DFNB28, DFNB30 and DFNB 31. Conclusion: In this research, the cause of additional 7% of non–syndromic hearing loss was determined in Iranian population.

Objective: Hereditary Hearing loss (HHL) affects one in 1000-2000 newborns and more than 50% of these cases, the loss has a genetic basis. About 70% of HHL is non-syndromic with autosomal recessive forms accounting for ~85% of the genetic load. To date, more than 100 locus estimated for this kind of deafness. Different genes have been reported to be involved, but mutations in the connexin 26 gene (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss. The aim of this project is to study the prevalence of connexin 26 mutations. Materials & Methods: In this study from the population that referred to welfare center of Khoozestan province for genetic counseling, 50 individual have been selected and getting 5-10 ml blood then after DNA extraction we analyzed quality of DNA by spectrophotometry. Mutation screening began by using Amplification Refractory Mutation System (ARMS) – Polymerase Chain Reaction (PCR) for detection of 35delG and then we analyzed all samples excluding 35delG homozygote by Denaturation High Polymorphic liquid Chromatography (DHPLC) and Direct Sequencing. Results: We screened 100 chromosomes (50 patients) for GJB2 mutations. Thirteen (13%) carry GJB2 mutations including 35delG, R184P, R32H, R127H, 300del2 (AT). Among them, 35delG has the highest frequency (61%). Polymorphism V153I was found in three chromosomes and also polymorphism V52V was found in family. Conclusion: According to our results, other loci and genes may be the major responsible for non-syndromic deafness in this population.