sanaz arzhangi

Cytoskeletal dynamics, the interplay of actin, microtubules, and septins, is a highly coordinated and tightly regulated process. Defects in the proteins involved can result in a wide range of cellular consequences. Hearing loss is the most common sensory defect and exhibits extraordinary genetic and phenotypic heterogeneity. Currently, there are more than 170 genes casually linked to non-syndromic hearing loss (NSHL), of which more than 60 are associated with autosomal dominant inheritance. Here, we add to this growing number by implicating MACF1 (OMIM # 608271), as a novel candidate gene for autosomal dominant non-syndromic hearing loss (ADNSHL). MACF1’s cytoskeleton integrator function and hair cell expression pattern lead one to believe that it is a necessary protein for hair cells. Many protein domains in MACF1 allow for dynamic interaction with the cytoskeleton. A large Iranian family segregating progressive ADNSHL was recruited for this study. The proband had bilateral mild-moderate sensorineural hearing loss and was negative for GJB2 mutations. After applying exome sequencing on the proband, a missense mutation c.1378C>T (p.His460Tyr) was found in MACF1 and co-segregated with the hearing loss in the extended family. We speculated that MACF1 mutations probably cause non-syndromic hearing loss inherited in an autosomal dominant manner. The potential functional impact of the identified variant will be investigated through further analysis.

 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.

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.

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.

 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.

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.

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.

The present research aimed to determine the effect of time-use training on the quality of time management in the mothers of girls with Intellectual Disability (ID) attending special schools. 

This was a quasi-experimental study with a control group design. In total, 80 mothers (40 mothers in the intervention group & 40 mothers in the control group) of children with ID (age range: 6-13 years) were studied. The study participants were selected by cluster sampling method. The required data were collected using a demographic data questionnaire and the Mothers’ Time Use Questionnaire (MTUQ). A time management training program was provided in a one-day workshop for the intervention group. The obtained data were analyzed in SPSS using Independent Samples t-test, Paired Samples t-test, and Chi-squared test.

After the intervention period, the quality of time management of the mothers in the intervention group significantly increased, compared to the controls (P<0.05).

The current research findings suggested that time-use training improved the quality of time management in the studied subjects. Therefore, educational interventions related to time management are recommended for the parents of children with ID. Besides, paying attention to this vulnerable group should be among nurses’ responsibilities.

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.

The parents of children with intellectual disabilities may have problems in effective use of their time and hence, suffer from varying levels of stress. This study aimed to evaluate the effects of time use training on stress among the mothers of female children with intellectual disabilities. In this experimental study, eighty mothers of school-age female children with intellectual disabilities were selected through cluster random sampling from two schools in the west of Tehran, Iran. They were randomly allocated either to a control or an intervention group. A six-hour time use training workshop was held for participants in the intervention group, while their counterparts in the control group did not receive any time use training. Data on participants’ time use and stress were collected before and six weeks after the intervention using the Mothers’ Time Use Questionnaire and the Questionnaire on Resources and Stress, respectively. The Chi-square, paired-sample t, and independent-samples t tests were used for data analysis. The mean score of time management quality in the intervention group significantly increased from 42.10 ± 6.46 to 46.80 ± 6.98 (P = 0.003) and the mean score of stress in this group significantly reduced from 29.3 ± 4.46 to 26.38 ± 5.67 (P = 0.007). However, none of these mean scores significantly changed in the control group (P > 0.05). The mothers of children with intellectual disability may benefit from time use training programs.

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.

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.

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. 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. GJB2-related deafness was found in 243 families (15.1%). 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)] hasnt been detected in our studied population.

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.