kimia kahrizi

Here, we report a case with concomitant variants: a novel homozygous HERC1 gene variant and a novel heterozygous PMP22 duplication. The 2-year-old male presented with seizures, developmental delay, macrocephaly, hypotonia, unilateral hypertrophy, thoracic scoliosis, normal brain MRI, and elevated homocysteine level which normalized after treatment. Whole exome sequencing (WES) revealed a co-occurrence of a homozygous novel likely pathogenic variant in the HERC1 gene (NM_003922.3:c.1280dup (p.ILe469Aspfs*33) and a novel heterozygous large duplication of exon 1-5 in the PMP22 gene, which has not been reported previously. The case underscores the challenges in understanding genotype-phenotype correlations and suggests a potential interplay between these genetic variants in shaping the current and future clinical phenotype of the patient. In the case of genetic diseases, this event may have important implications on family members’ counseling, and concomitant variants in Charcot–Marie–Tooth (CMT) families should be considered when significant intra-familial clinical heterogeneity is observed.

After GJB2, SLC26A4 is the second most common contributor to autosomal recessive nonsyndromic hearing loss (ARNSHL) worldwide. In this study, we used Exome Sequencing (ES) to present a village with 31 individuals affected by hereditary hearing loss (HHL) in southeastern Iran near the border of Pakistan. The village harbored the known pathogenic missense SLC26A4 (NM_000441.2):c.716T>A (p.Val239Asp) mutation, which has a founder effect attributed to Pakistan, Iran’s southeastern neighbor. Our findings, in addition to unraveling the molecular cause of non-syndromic hearing loss in these patients and further confirming the common ancestry and migration story between the people of this region and Pakistan, provide further insight into the genetic background of this region and highlight the importance of understanding the mutation spectrum of GJB2 and SLC26A4 in different regions to choose cost-effective strategies for molecular genetic testing.

 The study of Y-chromosomal variations provides valuable insights into male susceptibility in certain diseases like cardiovascular disease (CVD). In this study, we analyzed paternal lineage in different Iranian ethnic groups, not only to identify developing medical etiology, but also to pave the way for gender-specific targeted strategies and personalized medicine in medical genetic research studies.

 The diversity of eleven Iranian ethnic groups was studied using 27 Y-chromosomal short tandem repeat (Y-STR) haplotypes from Y-filer® Plus kit. Analysis of molecular variance (AMOVA) based on pair-wise RST along with multidimensional scaling (MDS) calculation and Network phylogenic analysis was employed to quantify the differences between 503 unrelated individuals from each ethnicity.

 Results from AMOVA calculation confirmed that Gilaks and Azeris showed the largest genetic distance (RST=0.35434); however, Sistanis and Lurs had the smallest considerable genetic distance (RST=0.00483) compared to other ethnicities. Although Azeris had a considerable distance from other ethnicities, they were still close to Turkmens. MDS analysis of ethnic groups gave the indication of lack of similarity between different ethnicities. Besides, network phylogenic analysis demonstrated insignificant clustering between samples.

 The AMOVA analysis results explain that the close distance of Azeris and Turkmens may be the effect of male-dominant expansions across Central Asia that contributed to historical and demographics of populations in the region. Insignificant differences in network analysis could be the consequence of high mutation events that happened in the Y-STR regions over the years. Considering the ethnic group affiliations in medical research, our results provided an understanding and characterization of Iranian male population for future medical and population genetics studies.

Intellectual disability (ID) represents a significant health challenge due to its diverse and intricate nature. A multitude of genes play a role in brain development and function, with defects in these genes potentially leading to ID. Considering that many of these genes have yet to be identified, and those identified have only been found in a small number of patients, no complete description of the phenotype created by these genes is available. CC2D1A is one of the genes whose loss-of-function mutation leads to a rare form of non-syndromic ID- 3(OMIM*610055), and four pathogenic variants have been reported in this gene so far.

In the current study, two affected females were included with an initial diagnosis of ID who were from an Iranian family with consanguineous marriage. Whole-exome sequencing was used to identify the probable genetic defects. The Genotypic and phenotypic characteristics of the patients were compared with a mutation in the CC2D1A gene, and then the structure of the gene and its reported variants were investigated.

The patients carried a novel homozygous splicing variant (NM_017721, c.1641+1G>A) in intron 14, which is pathogenic according to the ACMG guideline. Loss-of-function mutations in CC2D1A have severe phenotypic consequences such as ID, autism spectrum disorder (ASD),  and seizures. However, missense mutations lead to ASD with or without ID, and in some patients, they cause ciliopathy.

This study reports the fifth novel, probably pathogenic variant in the CC2D1A gene. Comparing the clinical and molecular genetic features of the patients with loss-of-function mutation helped to describe the phenotype caused by this gene more precisely. Investigating the CC2D1A gene's mutations and structure revealed that it performs multiple functions. The DM14 domain appears more pivotal in triggering severe clinical symptoms, including ID, than the C2 domain.

Charcot-Marie-Tooth disease type 4G (CMT4G) was first reported in Balkan Gypsies as a myelinopathy starting with progressive distal lower limb weakness, followed by upper limb involvement and prominent distal sensory impairment later in the patient’s life. So far, CMT4G has been only reported in European Roma communities with two founder homozygous variants; g.9712G>C and g.11027G>A, located in the 5’-UTR of the HK1 gene. Here, we present the first Iranian CMT4G patient manifesting progressive distal lower limb weakness from 11 years of age and diagnosed with chronic demyelinating sensorimotor polyneuropathy. Whole-exome sequencing for this patient revealed a homozygous c.19C>T (p. Arg7*) variant in the HK1 gene. This report expands the mutational spectrum of the HK1-related CMT disorder and provides supporting evidence for the observation of CMT4G outside the Roma population. Interestingly, the same Arg7* variant is recently observed in another unrelated Pakistani CMT patient, proposing a possible prevalence of this variant in the Middle Eastern populations.

 Intellectual disability (ID) is a genetically heterogeneous condition, and so far, 1679 human genes have been identified for this phenotype. Countries with a high rate of parental consanguinity, such as Iran, provide an excellent opportunity to identify the remaining novel ID genes, especially those with an autosomal recessive (AR) mode of inheritance. This study aimed to investigate the most prevalent ID genes identified via next-generation sequencing (NGS) in a large ID cohort at the Genetics Research Center (GRC) of the University of Social Welfare and Rehabilitation Sciences.

 First, we surveyed the epidemiological data of 619 of 1295 families in our ID cohort, who referred to the Genetics Research Center from all over the country between 2004 and 2021 for genetic investigation via the NGS pipeline. We then compared our data with those of several prominent studies conducted in consanguineous countries. Data analysis, including cohort data extraction, categorization, and comparison, was performed using the R program version 4.1.2.

 We categorized the most common ID genes that were mutated in more than two families into 17 categories. The most common syndromic ID in our cohort was AP4 deficiency syndrome, and the most common non-syndromic autosomal recessive intellectual disability (ARID) gene was ASPM. We identified two unrelated families for the 36 ID genes. We found 14 genes in common between our cohort and the Arab and Pakistani groups, of which three genes (AP4M1, AP4S1, and ADGRG1) were repeated more than once.

 To date, there has been no comprehensive targeted NGS platform for the detection of ID genes in our country. Due to the large sample size of our study, our data may provide the initial step toward designing an indigenously targeted NGS platform for the diagnosis of ID, especially common ARID in our population.

Genetic analysis of non-syndromic hearing loss (NSHL) has been challenged due to marked clinical and genetic heterogeneity. Today, advanced next-generation sequencing (NGS) technologies, such as exome sequencing (ES), have drastically increased the efficacy of gene identification in heterogeneous Mendelian disorders. Here, we present the utility of ES and re-evaluate the phenotypic data for identifying candidate causal variants for previously unexplained progressive moderate to severe NSHL in an extended Iranian family. Using this method, we identified a known heterozygous nonsense variant in exon 26 of the DIAPH1 gene (MIM: 602121), which led to “Deafness, autosomal dominant 1, with or without thrombocytopenia; DFNA1” (MIM: 124900) in this large family in the absence of GJB2 disease-causing variants and also OtoSCOPE-negative results. To the best of our knowledge, this nonsense variant (NM_001079812.3):c.3610C>T (p.Arg1204Ter) is the first report of the DIAPH1 gene variant for autosomal dominant non-syndromic hearing loss (ADNSHL) in Iran.

Ion channel dysfunction in the brain can lead to impairment of neuronal membranes and generate several neurological diseases, especially neurodevelopmental disorders.

In this study, we set out to delineate the genotype and phenotype spectrums of 14 Iranian patients from 7 families with intellectual disability (ID) and/or developmental delay (DD) in whom genetic mutations were identified by next-generation sequencing (NGS) in 7 channel-encoding genes: KCNJ10, KCNQ3, KCNK6, CACNA1C, CACNA1G, SCN8A, and GRIN2B. Moreover, the data of 340 previously fully reported ID and/or DD cases with a mutation in any of these seven genes were combined with our patients to clarify the genotype and phenotype spectrum in this group.

In total, the most common phenotypes in 354 cases with ID/DD in whom mutation in any of these 7 channel-encoding genes was identified were as follows: ID (77.4%), seizure (69.8%), DD (59.8%), behavioral abnormality (29.9%), hypotonia (21.7%), speech disorder (21.5%), gait disturbance (20.9%), and ataxia (20.3%). Electroencephalography abnormality (33.9%) was the major brain imaging abnormality.

The results of this study broaden the molecular spectrum of channel pathogenic variants associated with different clinical presentations in individuals with ID and/or DD.

Autosomal dominant polycystic kidney disease (ADPKD), one of the common inherited disorders in humans, is characterized by the development and enlargement of renal cysts, often leading to end-stage renal disease (ESRD). In this study, Iranian ADPKD families were subjected to high-throughput DNA sequencing to find potential causative variants facilitating the way toward risk assessment and targeted therapy.

Our protocol was based on the targeted next generation sequencing (NGS) panel previously developed in our center comprising 12 genes involved in PKD. This panel has been applied to investigate the genetic causes of 32 patients with a clinical suspicion of ADPKD.

We identified a total of 31 variants for 32 individuals, two of which were each detected in two individuals. Twenty-seven out of 31 detected variants were interpreted as pathogenic/likely pathogenic and the remaining 4 of uncertain significance with a molecular diagnostic success rate of 87.5%. Among these variants, 25 PKD1/2 pathogenic/likely pathogenic variants were detected in 32 index patients (78.1%), and variants of uncertain significance in four individuals (12.5% in PKD1/2). The majority of variants was identified in PKD1 (74.2%). Autosomal recessive PKD was identified in one patient, indicating the similarities between recessive and dominant PKD. In concordance with earlier studies, this biallelic PKD1 variant, p.Arg3277Cys, leads to rapidly progressive and severe disease with very early-onset ADPKD.

Our findings suggest that targeted gene panel sequencing is expected to be the method of choice to improve diagnostic and prognostic accuracy in PKD patients with heterogeneity in genetic background.

Intellectual disability (ID) is a heterogonous disorder with complex etiology. The frequency of autosomal recessive inheritance defects was elevated in a consanguineous family.

In this study, high-throughput DNA sequencing was performed in an Iranian consanguineous family with two affected individuals to find potential causative variants. Whole-exome sequencing was carried out on the proband and Sanger sequencing was implemented for validation of the likely causative variant in the family members.

A novel homozygous missense mutation (p.Arg122Trp) was detected in the PTRHD1 gene.

PTRHD1 has been recently introduced as a candidate ID and Parkinsonism causing gene. Our findings are in agreement with the clinical spectrum of PTRHD1 mutations; however, our affected individuals suffer from ID manifestations.

Neurodevelopmental and intellectual impairments are extremely heterogeneous disorders caused by a diverse variety of genes involved in different molecular pathways and networks. Genetic alterations in cilia, highly-conserved organelles with sensorineural and signal transduction roles can compromise their proper functions and lead to so-called “ciliopathies” featuring intellectual disability (ID) or neurodevelopmental disorders as frequent clinical manifestations. Here, we report several Iranian families affected by ID and other ciliopathy-associated features carrying known and novel variants in two ciliary genes; CEP104 and CEP290.

Whole exome and targeted exome sequencing were carried out on affected individuals. Lymphoblastoid cell lines (LCLs) derived from the members of affected families were established for two families carrying CEP104 mutations. RNA and protein expression studies were carried out on these cells using qPCR and Western blot, respectively.

A novel homozygous variant; NM_025114.3:c.7341_7344dupACTT p.(Ser2449Thrfs*8) and four previously reported homozygous variants; NM_025114.3:c.322C>T p.(Arg108*), NM_025114.3:c.4393C>T p.(Arg1465*), NM_025114.3:c.5668G>T p.(Gly1890*) and NM_025114.3:c.1666dupA p.(Ile556Asnfs*20) were identified in CEP290. In two other families, two novel homozygous variants; NM_014704:c.2356_2357insTT p.(Cys786Phefs*11) and NM_014704:c.1901_1902insT p.(Leu634Phefs*33) were identified in CEP104, another ciliary gene. qPCR and Western blot analyses showed significantly lower levels of CEP104 transcripts and protein in patients compared to heterozygous or normal family members.

We emphasize the clinical variability and pleiotropic phenotypes due to the variants of these genes. In conclusion, our findings support the pivotal role of these genes in cognitive and neurodevelopmental features.

Cerebrotendinous xanthomatosis (CTX) is a rare congenital lipid-storage disorder, leading to a progressive multisystem disease. CTX with autosomal recessive inheritance is caused by a defect in the CYP27A1 gene. Chronic diarrhea, tendon xanthomas, neurologic impairment, and bilateral cataracts are common symptoms of the disease.

Three affected siblings with an initial diagnosis of non-syndromic intellectual disability were recruited for further molecular investigations. To identify the possible genetic cause(s), whole exome sequencing was performed on the proband. Sanger sequencing was applied to confirm the final variant. The clinical and molecular genetic features of the three siblings from the new CTX family and other patients with the same mutations, as previously reported, were analyzed. The CYP27A1 gene was also studied for the number of pathogenic variants and their location.

We found a homozygous splicing mutation, NM_000784: exon6: c.1184+1G>A, in CYP27A1 gene, which was confirmed by Sanger sequencing. Among the detected pathogenic variants, the splice site mutation had the highest prevalence, and the mutations were mostly found in exon 4.

This study is the first to report the c.1184+1G>A mutation in Iran. Our findings highlight the other feature of the disease, which is the lack of relationship between phenotype and genotype. Due to nonspecific symptoms and delay in diagnosis, CYP27A1 genetic analysis should be the definitive method for CTX diagnosis.

Recently, we have reported mutations in LARP7 gene, leading to neurodevelopmental disorders (NDDs), the most frequent cause of disability in children with a broad phenotype spectrum and diverse genetic landscape.

Here, we present two Iranian patients from consanguineous families with syndromic intellectual disability, facial dysmorphism, and short stature.

Whole-exome sequencing (WES) revealed a novel homozygous stop-gain (c.C925T, p.R309X) variant and a previously known homozygous acceptor splice-site (c.1669-1_1671del) variant in LARP7 gene, indicating the diagnosis of Alazami syndrome.

These identified variants in patients with Alazami syndrome were consistent with previously reported loss of function variants in LARP7 and provide further evidence that loss of function of LARP7 is the disease mechanism.

Inherited peripheral neuropathies (IPNs) are a group of neuropathies affecting peripheral motor and sensory neurons. Charcot-Marie-Tooth (CMT) disease is the most common disease in this group. With recent advances in next-generation sequencing (NGS) technologies, more than 100 genes have been implicated for different types of CMT and other clinically and genetically inherited neuropathies. There are also a number of genes where neuropathy is a major feature of the disease such as spinocerebellar ataxia (SCA) and hereditary spastic paraplegia (HSP). We aimed to determine the genetic causes underlying IPNs in Iranian families.

We performed whole exome sequencing (WES) for 58 PMP22 deletion-/duplication-negative unrelated Iranian patients with a spectrum of phenotypes and with a preliminary diagnosis of hereditary neuropathies.

Twenty-seven (46.6%) of the cases were genetically diagnosed with pathogenic or likely pathogenic variants. In this study, we identified genetically strong variants within genes not previously linked to any established disease phenotype in five (8.6%) patients.

Our results highlight the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs. Moreover, functional analysis is required for novel and uncertain variants.

Ménière’s disease (MD) is a common inner ear disorder which is characterized by recurrent attacks of vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and a sense of fullness in the affected ear. MD is a complex disorder; although six genes have been linked to familial autosomal dominant form of the disease, in many cases, the exact genetic etiology remains elusive.

To elucidate the genetic causes of MD in an Iranian family, we performed exome sequencing on all members of the family: consanguineous parents and four children (two affected and two unaffected). Variant filtering was completed using a customized workflow keeping variants based on segregation with MD in autosomal recessive (AR) inheritance pattern, minor allele frequency (MAF), and in-silico prediction of pathogenicity.

Analysis revealed that in this family, 970 variants co-segregated with MD in AR pattern, out of which eight variants (one intergenic, four intronic, and three exonic) were extremely rare. The exonic variants included a synonymous substitution in USP3 gene, an in-frame deletion in ZBED2 gene, and a rare, highly conserved deleterious missense alteration in LSAMP gene.

The phenotype observed in the proband described here, i.e. vertigo, poor sense of smell, tinnitus, and borderline hearing ability, may originate from aberrant changes in the cerebellum and limbic system due to a deleterious mutation in the LSAMP gene; hence, LSAMP mutation is a possible candidate for the etiology of MD in this family.

Many genes with different inheritance modes contribute to the pathogenicity of intellectual disability (ID) making it the most known genetically heterogeneous disorder. Advanced next-generation sequencing (NGS) technologies have helped researchers identify genes underlying ID at an exponential pace. As a consanguineous country, Iran is a hotspot for discovering novel autosomal recessive intellectual disability (ARID) genes. Here, we aimed to review and compare reported ARID gene discovery both in Iran and globally, and pinpoint the research areas that need to be developed in future. We studied published articles and reviews on all known ID genes. In parallel, the gene-discovery research carried out on the Iranian population were also reviewed to determine the contribution of Iran to identifying novel ID genes. Also we tried to find supporting evidence on the causative role of novel genes identified in Iran including confirmatory functional studies and existence of more affected families. We also briefly reviewed the current therapeutic approaches under development for a subset of eligible ID cases. In total, 8% of all ID and 11.5% of all ARID genes described so far have been identified via studies on Iranian population. Functional studies have been performed on 29% of the genes identified in Iran. More than one affected family has been reported for many of these genes, supporting their causative role in ID pathogenesis. Despite the notable contribution of Iran in gene-discovery research, further functional studies on the identified genes are required.

Hearing loss (HL) is the most common sensory deficit in humans, and genetic factors contribute to about half of the cases. With 112 causative genes identified so far and a disproportionate share of the genes within different ethnic groups, HL has proven to be quite heterogeneous. Twenty Iranian families having at least 2 children with hereditary HL were initially verified to be GJB2-negative and were then subjected to whole exome sequencing (WES). Sanger sequencing was used to confirm segregation of the variant identified in each family. In 3 families, WES revealed 3 novel variants in KCNQ4, LHFPL5 and COCH genes. The KCNQ4 gene (DFNA2A) encodes a potassium channel (KV7.4) and the heterozygous variant identified (c.1647C>G, p.F549L) resulted in the substitution of Phe549 residing in the KV7.4 cytoplasmic region. The homozygous variant (c.34A>T, p.K12X) was identified in the LHFPL5 gene (DFNB67) which encodes a transmembrane protein, and another variant in a homozygous state (c.116T>A, p.L39X) was identified in the COCH gene which encodes a secretory protein. Pathogenic variants in the COCH gene are associated with late onset autosomal dominant hearing loss (DFNA9) but the affected individuals displayed early onset HL with a recessive mode of inheritance. The 16% contribution of GJB2 to HL in the Iranian population necessitates the discovery of the remaining causal factors. This study is the first to report KCNQ4 and COCH related HL in the Iranian population and the second study, globally, to report HL due to biallelic inactivation of the COCH gene.

In all organisms, transfer RNA (tRNA) molecules are required to undergo post-transcriptional modifications at different levels in order to convert into mature tRNAs. These modifications are critical for many aspects of tRNA function and structure, such as translational efficiency, flexibility, codon–anticodon interaction, stability, and fidelity. Up to now, over 100 modified nucleosides have been identified in tRNAs from all domains of life. Post-transcriptional modifications include different chemical processes such as methylation, deamination, or acetylation, with methylation reactions as the most common. tRNA methyltransferases are a family of enzymes involved in the post-transcriptional methylation of tRNA bases. Recent studies have reported different human diseases resulting from defects in tRNA methyltransferase activity, including cancer, diabetes and neurological disorders such as intellectual disability (ID). In this article, we focused on biological function and characterization of tRNA methyltransferases associated with ID in order to explain how functional disruption of tRNA methyltransferases could lead to ID phenotype.

Calpains are a group of non-lysosomal Ca2+dependent cysteine proteases with numerous substrates. Calpains have been identified in almost all eukaryotes and bacteria but not in archaebacteria. In the human genome, this group of enzymes has 15 isoforms and is present ubiquitously and demonstrates tissue-specific patterns of expression. Calpains are involved in different physiological and pathological processes such as cell proliferation, migration, invasion, apoptosis and signal transduction and their roles in various disorders have been reported. In this review, functions of calpains, their substrates, their mechanism of regulation and their involvement in diseases have been summarized.

Intellectual disability (ID) is a common and highly heterogeneous neurodevelopmental disorder. The prevalence of ID is around 1%–3% in the general population. ID is associated with a wide range of additional neurological disabilities and the results of various studies have disclosed the co-morbidity of ID and ataxia. The aim of this review is elucidation of the common molecular and cellular pathways in the etiology of ID and ataxia. Categorization of these genes with various cellular functions indicates several genetic collisions in the co-occurrence of ID and ataxia.

A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment.

With prevalence figures close to 0.2% at birth, hearing loss (HL) is the most frequent sensory impairment in childhood. In developed countries, genetic causes account for more than 60% of congenital HL, most often resulting in non-syndromic deafness, which is usually autosomal recessive.
Hereditary nonsyndromic hearing loss (NSHL) in Iran is highly heterogeneous, rendering molecular diagnosis difficult. Whole-exome sequencing (WES) has recently opened a new page in Mendelian disease gene discovery – enabling to study autosomal recessive HL in a new way. The aim of this study is to find more causative genes and their mutations for NSARHL in ten Iranian families by WES.
After DNA extraction and ruling out for prevalent mutations related to NSARHL in Iranian population, the proband of each family has been subjected to WES. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and Annovar.
Normative population databases (eg, 1000 Genomes SNP database, dbSNP, and HapMap) were used for comparison. The pathogenicity of variants was predicated using bioinformatics software such as SIFT, PolyPhen, ConSeq, CADD, GRPEE, dbNSFP and so on. Candidate pathogenetic variants have been co-segregate in families using Sanger Sequencing.
Result & A homozygous missense mutation in SLC26A4 and a novel mutation in PTPRQ genes identified in two families and confirmed by Sanger sequencing. Data analysis revealed a novel stop codon mutation in MYO7A gene in a family but co- segregation analysis failed to confirm this variant as the only cause of hearing loss in this family. Further clinical examination showed that the phenotypic variations in family exist and therefore involvement of 2 different genes causing both syndromic and non-syndromic hearing loss is possible. In addition, two novel candidate genes resulting hearing loss have been identified in two families. Further studies for confirmation of the pathogenecity of these variations and data analysis of remaining families are under investigation.

Neuromuscular disorders (NMDs) include a broad range of diseases affecting muscles, nerves and neuromuscular junctions. Approximately 761 different disorders occur in this group which is subdivided into 16 different subgroups with 406 known genes. NMDs are genetically and clinically heterogeneous conditions. The advent of next generation sequencing (NGS) approaches has accelerated the pace of discovery of NMDs genes. In this study, we describe the validation of an NGS panel, for comprehensive mutation detection in NMDs patients. During a year, a total of 46 patients were examined, mostly offspring of consanguineous marriages. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes. Co-segregation analysis and genotype–phenotype correlation led to identification of causal variants. In 33 out of 46 patients (71.7%), the pathogenic variant was identified in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected which is quite high compared to the overall diagnostic yield of no more than 50% in most other reports.

Hearing loss (HL) is the most common communication disorder affecting about 1/1000 births worldwide caused by environmental or genetic factors. About 30-50% is attributed to genetic factors and till now more than 85 genes have been implicated in non-syndromic HL. In Iran, HL is second to intellectual disability as the most common disability, affecting 1 of every 166 persons. About 15 years ago the studies of genes causing deafness have been started in Genetics Research Center (GRC) of University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Over 2500 families with hereditary HL have been referred to GRC from different parts of Iran. Almost all families have been investigated for the frequency of GJB2 gene mutations.The mutation in this gene is the most prevalent gene causing hereditary HL (HHL) in Iran. Total of 395 families had GJB2 gene mutations. The prevalence of GJB2-related deafness is relatively low in our country comparison with North American and European countries. We have also determined the prevalence of other known genes in our heterogeneous population.
In order to determine Iranian AR hereditary HL gene spectrum we used a custom targeted genomic enrichment panel which included all the 116 known HHL genes. A total of 302 GJB2-negative families were selected to be studied using targeted NGS panel. We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. Taken together, it can be concluded that the overall diagnosis rate of HHL in Iran is about 83%. The families which failed to identify plausible disease-causing variants using targeted NGS are a valuable cohort for novel deafness-gene discovery. Among them 23 families have been subjected to whole exome sequencing till now for whom we have identified 7 novel genes so far. In conclusion it should be mentioned that we have identify over 83% of Hereditary hearing loss genes in Iranian population and we have already identify number of candidate genes for the remaining 17% of the families.

Intellectual Disability (ID, also known as mental retardation) is a debilitating neurodevelopmental disorder affecting nearly 1% of the general population worldwide. Occurrence of behavioral disorders in individuals with ID is four times higher than that in the general population. An increasing number of studies seek to find a common pathway to elucidate brain structure/function and its contribution to behavior. This article deals with different behavioral disorders reported in individuals with syndromic and non-syndromic ID and possible candidate genes, most of which are involved in synaptic formation and function. Many ID cases with behavior impairments were referred to genetic centers to identify genetic causes; therefore, the authors gathered data from their own studies along with similar published reports, to provide a review on genes involved in brain development and cognition. In this study, we argued how defects in genes with diverse functional role may contribute to behavior impairments and a brain malfunction. Evidences from individual with cognitive impairment as well as murine and drosophila animal models have been used to show behavioral consequences of functional deficits in genes speculated to play a role in cognition and learning.