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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.

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.

Background Hereditary hearing loss (HHL) is a clinically and genetically heterogeneous sensorineural disorder that presents challenges for diagnosis. Next‐generation sequencing (NGS) approaches have facilitated a more cost‐effective, streamlined diagnostic process. This study aimed to identify HHL variants using NGS in Iranian Azeri families in Ardabil Province, establishing a suitable framework for screening programs tailored to the local population. Methods Seventy‐four GJB2‐negative Azeri families with HHL from Ardabil Province of Iran were studied using the OtoSCOPE panel and/or exome sequencing over 15‐years from 2008 to 2023. Results Data analysis revealed 53 HHL variants in 52 of the 74 most consanguineous families (70%), including 34 pathogenic/likely pathogenic variants and 19 variants of uncertain significance. Seventeen of the detected variants were novel. SLC26A4, MYO7A, USH2A, and TMPRSS3 were the most prevalent mutated genes for non‐syndromic hearing loss (NSHL) and syndromic hearing loss (SHL) in this study. Conclusion Our results are comparable to those of previous studies, indicating that SLC26A4 is the second most common cause of HHL, after GJB2. Moreover, our study emphasizes the significance of understanding the genetic basis of HL for early diagnosis and the implementation of suitable screening programs for various ethnicities in Iran. Our study highlights that SLC26A4 is the second most prevalent cause of hearing loss, following GJB2. This finding underscores the significance of understanding the genetic underpinnings of hearing loss for early diagnosis and the implementation of appropriate screening programs for different ethnic groups in Iran.

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. We report a duplication on the X chromosome encompassing Xq13.2q13.3 in a large Iranian family with X‐linked intellectual disability. There are seven affected males in ones and twos within two generations of the pedigree who presented with a similar phenotype, including ID, short stature, seizures, facial anomalies, behavioral abnormalities, speech impairment, and micropenis.

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

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.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

BackgroundCountries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes.DesignUsing a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families.ResultsWe 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. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion–deletion variants and three novel CNV. Several variants represent founder mutations.ConclusionThis study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.

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.