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Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype–phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.

Cellular action potential is characterized by a particular sequence of depolarizing and repolarizing ion currents regulated by ion channels. Genetic mutations in these channels disrupt the essential movement of ions, such as Na+, Ca++, and K+, across the cell membrane, leading to dangerous arrhythmias and sudden cardiac death (SCD). Most cases of unexplained SCD are caused by pathogenic variants in genes linked to channelopathies and cardiomyopathy. Genetic investigations might aid in confirming the clinical diagnosis based solely on observations. Other advantages of genetic studies are clinical management of the patient, family screening, appropriate genetic counseling, and risk assessment for family members. This study was conducted to investigate the genetic cause of early‐onset SCD in two Iranian families. Whole‐exome sequencing was performed on the probands from each family, and the Illumina DRAGEN haplotype variant calling system was used to identify variants in each patient. Here, we identified rare heterozygous missense variants in the RYR2 and SCN5A genes, which are linked to cardiac channelopathies. Alignment studies reveal that the mutated residues are conserved across humans and primates, underscoring their crucial role in protein function. Previously reported associations between these mutations and channelopathy pathogenesis have been confirmed in the present study. This study provides valuable insights for genetic counseling of families with a history of sudden death.

Background: PMM2-CDG, also known as congenital disorder of glycosylation type 1a, is the most common N-linked glycosylation disorder, characterized by a wide range of neurological and multisystem manifestations. Understanding the genotype-phenotype correlations is essential for accurate diagnosis and patient management. This study aims to identify the genetic cause of PMM2-CDG in an Iranian family with multiple affected members, and to analyze the genetic and clinical spectrum of the disorder through a comprehensive literature review. Methods: Exome sequencing re-analysis was performed to detect disease-causing variants in three affected siblings. Additionally, a literature review was conducted, analyzing 91 previously reported cases of PMM2-CDG to determine the most prevalent variants and associated clinical features. Results: A novel splice site variant (c.640-9T>A) was identified alongside a previously reported missense mutation (c.647A>T; p.N216I) in the affected individuals. The literature review revealed that the most frequent PMM2 variants were p.R141H (28.8%), p.V231M (12.8%), p.N216I (6.4%), and p.V129M (5.8%), with 77.6% of mutations occurring in exons 5 and 8. The most common clinical findings included developmental delay, ocular abnormalities (hypertelorism, strabismus), muscular system defects (hypotonia, muscle weakness), neurological symptoms (abnormal MRI findings), cardiovascular involvement (pericarditis, pericardial effusion), and clotting disorders. Conclusion: We expect that our detailed clinical study will improve the genotype-phenotype interpretation of causal PMM2-CDG variants and the analysis of next-generation sequencing data, leading to clarification of the cause of complicated cases of rare diseases.

Intellectual disability (ID) affects approximately 1%–3% of the population and spans diverse clinical presentations with marked genetic heterogeneity, especially in consanguineous populations where autosomal‐recessive ID is common. Despite advances in diagnostic methods, ~50% of individuals with ID remain without a molecular diagnosis. Genome sequencing (GS) can detect variant classes poorly captured by other methodologies, including deep intronic splice changes and structural variants. We performed short‐read GS on 38 Iranian autosomal recessive intellectual disability (ARID) families that remained unsolved after exome sequencing (ES) and two phases of reanalysis. Sequencing and variant calling were performed on DRAGEN Bio‐IT Platform with GRCh38 and variants were annotated in Golden helix Varseq software and the AnnotSV tool. GS yielded diagnoses in 2 of 38 families (5.3%), identifying a homozygous deep‐intronic ATP8A2 variant (c.1473 + 519C > T) that creates a cryptic donor site and a 57‐bp pseudoexon, and a homozygous ~103‐kb CNTNAP2 deletion removing the in‐frame Exon 2. Additionally, GS uncovered a homozygous NCOR1 missense variant that represents a novel candidate gene for ARID, but further studies are required to confirm the gene–disease association. The ATP8A2 and CNTNAP2 variants were uniquely detectable by GS. In conclusion, in a challenging, ES‐negative ARID cohort, GS provided an additional ~5.3% diagnostic yield by uncovering a noncoding splice alteration and a large intragenic deletion. These results underscore GS as a valuable, though still modest, tool over ES and highlight significant interpretation challenges in noncoding regions. Continued advances in functional assays and complementary long‐read technologies will be essential to further reduce the diagnostic gap in unresolved ID.

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.

Background: 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. Methods: 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: 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. Conclusion: 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.

Background: Complete SARS-CoV-2 genome sequencing in the early phase of the outbreak in Iran showed two independent viral entries. Subsequently, as part of a genome surveillance project, we aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year after emerging. Methods: We provided 319 SARS-CoV-2 whole-genome sequences used to monitor circulating lineages in March 2020-May 2021 time interval. Results: The temporal dynamics of major SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and represent the 19A clade (B.4) dominating the first disease wave, followed by 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7), leading the second, third and fourth waves, respectively. We observed a mixture of circulating B.1.36, B.1.1.413, B.1.1.7 lineages in winter 2021, paralleled in a fading manner for B.1.36/B.1.1.413 and a growing rise for B.1.1.7, prompting the fourth outbreak. Entry of the Delta variant, leading to the fifth disease wave in summer 2021, was detected in April 2021. This study highlights three lineages as hallmarks of the SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (B.1.1 with the combination of [D138Y-S477N-D614G] spike mutations) as a characterizing lineage in Iran, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. It also designates the renowned combination of G and GR clades’ mutations as the top recurrent mutations. Conclusion: In brief, we provided a real-time and comprehensive picture of the SARS-CoV-2 genetic diversity in Iran and shed light on the SARS-CoV-2 transmission and circulation on the regional scale.

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.

Background: Global real-time monitoring of SARS-CoV-2 variants is crucial to controlling the COVID-19 outbreak. The purpose of this study was to set up a Sanger-based platform for massive SARS-CoV-2 variant tracking in laboratories in low-resource settings. Methods: We used nested RT-PCR assay, Sanger sequencing and lineage assignment for 930-bp of the SARS-CoV-2 spike gene, which harbors specific variants of concern (VOCs) mutations. We set up our platform by comparing its results with whole genome sequencing (WGS) data on 137 SARS-CoV-2 positive samples. Then, we applied it on 1028 samples from March-September 2021. Results: In total, 125 out of 137 samples showed 91.24% concordance in mutation detection. In lineage assignment, 123 out of 137 samples demonstrated 89.78% concordance, 65 of which were assigned as VOCs and showed 100% concordance. Of 1028 samples screened by our in-house method, 78 distinct mutations were detected. The most common mutations were: S:D614G (21.91%), S:P681R (12.19%), S:L452R (12.15%), S:T478K (12.15%), S:N501Y (8.91%), S:A570D (8.89%), S:P681H (8.89%), S:T716I (8.74%), S:L699I (3.50%) and S:S477N (0.28%). Of 1028 samples, 980 were attributed as VOCs, which include the Delta (B.1.617.2) and Alpha (B.1.1.7) variants. Conclusion: Our proposed in-house Sanger-based assay for SARS-CoV-2 lineage assignment is an accessible strategy in countries with poor infrastructure facilities. It can be applied in the rapid tracking of SARS-CoV-2 VOCs in the SARS-CoV-2 pandemic.