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SARS-CoV-2 genome surveillance projects provide a good measure of transmission and monitor the circulating SARS-CoV-2 variants at regional and global scales. Iran is one of the most affected countries still involved with the virus circulating in at least five significant disease waves, as of September 2021. Complete genome sequencing of 50 viral isolates in an early phase of outbreak in Iran, shed light on the origins and circulating lineages at that time. As part of a genomic surveillance program, we provided an additional 319 complete genomes from October 2020 onwards. The current study is the report of complete SARS-CoV-2 genome sequences of Iran in the March 2020-May 2021 time interval. We aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year. Overall, 35 different lineages and 8 clades were detected. Temporal dynamics of the prominent SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and introduces 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) clades, dominating second, third and fourth disease waves, respectively. We observed a mixture of circulating 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7) clades in winter 2021, paralleled in a diminishing manner for 20A/20B and a growing rise for 20I, eventually prompting the 4th outbreak peak. Furthermore, our study provides evidence on the entry of the Delta variant in April 2021, leading to the 5th disease wave in summer 2021. Three lineages are highlighted as hallmarks of SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (specific B.1.1 lineage carrying a combination of [D138Y-S477N-D614G] spike mutations) in October 2020-February 2021, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. Continuous monthly monitoring of SARS-CoV-2 genome mutations led to the detection of 1577 distinct nucleotide mutations, in which the top recurrent mutations were D614G, P323L, R203K/G204R, 3037C>T, and 241C>T; the renowned combination of mutations in G and GH clades. The most frequent spike mutation is D614G followed by 13 other frequent mutations based on the prominent circulating lineages; B.1.1.7 (H69_V70del, Y144del, N501Y, A570D, P681H, T716I, S982A, D1118H, I100T, and L699I), B.1.1.413 (D138Y, S477N) and B.1.36 (I210del). In brief, mutation surveillance in this study provided a real-time comprehensive picture of the SARS-CoV-2 mutation profile in Iran, which is beneficial for evaluating the magnitude of the epidemic and assessment of vaccine and therapeutic efficiency in this population.

The SARS‐CoV‐2 virus has been rapidly spreading globally since December 2019, triggering a pandemic, soon after its emergence. While Iran was among the first countries confronted with rapid spread of virus in February 2020, no real‐time SARS‐CoV‐2 whole‐genome tracking in early phase of outbreak was performed in the country. To address this issue, we provided 50 whole‐genome sequences of viral isolates ascertained from different geographical locations in Iran during March–July 2020. The corresponding analysis on origins, transmission dynamics and genetic diversity of SARS‐CoV‐2 virus, represented at least two introductions of the virus into the country, constructing two major clusters defined as B.4 and B.1*. The first entry of the virus might have occurred around very late 2019/early 2020, as suggested by the time to the most recent common ancestor, followed by a rapid community transmission that led to dominancy of B.4 lineage in early epidemic till the end of June. Gradually, reduction in dominancy of B.4 occurred possibly as a result of other entries of the virus, followed by surge of B.1* lineages, as of mid‐May. Remarkably, variation tracking of the virus indicated the increase in frequency of D614G mutation, along with B.1* lineages, which showed continuity till October 2020. The increase in frequency of D614G mutation and B.1* lineages from mid‐May onwards predicts a rapid viral transmission that may push the country into a critical health situation followed by a considerable change in composition of viral lineages circulating in the country.

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.

Objective Hereditary hearing loss is the most common neurosensory disorder in humans caused by myriad mutations in numerous genes. Autosomal recessive nonsyndromic hearing loss (ARNSHL) accounts for 80% of hearing impairments of genetic origin and is quite prevalent in societies with a high rate of consanguinity. In the current study, we investigated the causes of sensorineural hearing loss in 24 unrelated Iranian families who were mainly consanguineous and had at least two affected children. Methods All probands were initially screened for GJB2 mutations, as the most common causes of ARNSHL in Iran. Verified GJB2-negative samples were subsequently subjected to whole exome sequencing (WES) to identify the underlying causes of hearing impairment, and the variants identified in each family were further confirmed by Sanger sequencing. Results WES revealed three previously unreported mutations in MYO15A, the gene encoding the unconventional myosin 15 (Myo15). All variants identified, c.C6436T (p.R2146W), c.C9584G (p.P3195R) and c.G10266C (p.Q3422H), reside in the MYTH4 (myosin tail homology) and FERM (4.1 ezrin, radixin, moesin) domains of the protein. Conclusion Globally, mutations in MYO15A are considered to be among the most prevalent genetic causes of ARNSHL, and they rank as the third leading cause of hearing loss in the Iranian population, below GJB2 and SLC26A4. Yet again, these results endorse the importance of MYO15 screening in hearing impaired populations, particularly in Iran.

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.

The SARS-CoV-2 virus has been rapidly spreading globally since December 2019, triggering a pandemic, soon after its emergence, with now more than one million deaths around the world. While Iran was among the first countries confronted with rapid spread of virus in February, no real-time SARS-CoV-2 whole-genome tracking is performed in the country.To address this issue, we provided 50 whole-genome sequences of viral isolates ascertained from different geographical locations in Iran during March-July 2020. The corresponding analysis on origins, transmission dynamics and genetic diversity, represented at least two introductions of the virus into the country, constructing two major clusters defined as B.4 and B.1*. The first entry of the virus occurred around 26 December 2019, as suggested by the time to the most recent common ancestor, followed by a rapid community transmission, led to dominancy of B.4 lineage in early epidemic till the end of June. Gradually, reduction in dominancy of B.4 occurred possibly as a result of other entries of the virus, followed by surge of B.1.* lineages, as of mid-May.Remarkably, variation tracking of the virus indicated the increase in frequency of D614G mutation, along with B.1* lineages, which showed continuity till October 2020.According to possible role of D614G in increased infectivity and transmission of the virus, and considering the current high prevalence of the disease, dominancy of this lineage may push the country into a critical health situation. Therefore, current data warns for considering stronger prohibition strategies preventing the incidence of larger crisis in future.

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

Considering the application of human genome variation databases in precision medicine, population-specific genome projects are continuously being developed. However, the Middle Eastern population is underrepresented in current databases. Accordingly, we established Iranome database (www.iranome.com) by performing whole exome sequencing on 800 individuals from eight major Iranian ethnic groups representing the second largest population of Middle East. We identified 1,575,702 variants of which 308,311 were novel (19.6%). Also, by presenting higher frequency for 37,384 novel or known rare variants, Iranome database can improve the power of molecular diagnosis. Moreover, attainable clinical information makes this database a good resource for classifying pathogenicity of rare variants. Principal components analysis indicated that, apart from Iranian-Baluchs, Iranian-Turkmen, and Iranian-Persian Gulf Islanders, who form their own clusters, rest of the population were genetically linked, forming a super-population. Furthermore, only 0.6% of novel variants showed counterparts in "Greater Middle East Variome Project", emphasizing the value of Iranome at national level by releasing a comprehensive catalog of Iranian genomic variations and also filling another gap in the catalog of human genome variations at international level. We introduce Iranome as a resource which may also be applicable in other countries located in neighboring regions historically called Greater Iran (Persia).

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.1647CG, p.F549L) resulted in the substitution of Phe549 residing in the KV7.4 cytoplasmic region. The homozygous variant (c.34AT, p.K12X) was identified in the LHFPL5 gene (DFNB67) which encodes a transmembrane protein, and another variant in a homozygous state (c.116TA, 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.

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., Author summary Based on genome-wide genotype data on over 1000 samples from eleven ethnic groups present in Iran and by comparison to reference data sets of both extant populations and ancient DNA samples, we show that the Iranian population comprises distinct genetic variation with respect to populations in close geographic proximity, a cluster of genetically largely overlapping ethnic groups as well as a number of strongly admixed groups. These observations, also corroborated by f3 migration statistics and other approaches, indicate genetic continuity of and limited influx into the cluster groups over several millennia, despite Iran’s geographic position at a crossroads in West Asia. They also suggest, correspondingly, several instances of language adoption instead of demic replacement in the past. Future human genetic studies, both with a focus on population and medical genetics, will have to consider differences in heterogeneity, consanguinity and degree of admixture between the ethnic groups for an adequate design and interpretation.

MYO15A is located at the DFNB3 locus on chromosome 17p11.2, and encodes myosin-XV, an unconventional myosin critical for the formation of stereocilia in hair cells of cochlea. Recessive mutations in this gene lead to profound autosomal recessive nonsyndromic hearing loss (ARNSHL) in humans and the shaker2 (sh2) phenotype in mice. Here, we performed a study on 140 Iranian families in order to determine mutations causing ARNSHL. The families, who were negative for mutations in GJB2, were subjected to linkage analysis. Eight of these families showed linkage to the DFNB3 locus, suggesting a MYO15A mutation frequency of 5.71% in our cohort of Iranian population. Subsequent sequencing of the MYO15A gene led to identification of 7 previously unreported mutations, including 4 missense mutations, 1 nonsense mutation, and 2 deletions in different regions of the myosin-XV protein.

Objective Hereditary hearing impairment is a genetically heterogeneous disorder. In spite of this, mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of nonsyndromic recessive hearing loss in many countries and are largely dependent on ethnic groups. The purpose of our study was to characterize the type and prevalence of GJB2 mutations among Azeri population of Iran. Methods Fifty families presenting autosomal recessive nonsyndromic hearing loss from Ardabil province of Iran were studied for mutations in GJB2 gene. All DNA samples were screened for c.35delG mutation by ARMS PCR. Samples from patients who were normal for c.35delG were analyzed for the other variations in GJB2 by direct sequencing. In the absence of mutation detection, GJB6 was screened for the del(GJB6-D13S1830) and del(GJB6-D13S1854). Result Thirteen families demonstrated alteration in the Cx26 (26%). The 35delG mutation was the most common one, accounting for 69.2% (9 out of 13 families). All the detected families were homozygous for this mutation. Two families were homozygous for delE120 and 299–300delAT mutations. We also identified a novel mutation: c.463–464 delTA in 2 families resulting in a frame shift mutation. Conclusion Our results suggest that c.35delG mutation in the GJB2 gene is the most important cause of GJB2 related deafness in Iranian Azeri population.

Mutations in GJB2 are a major cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of GJB2 mutations that are associated with ARNSHL in Caucasians in many European countries and also in Iranian. In this study, we used PCR and restriction digestion to genotype five single nucleotide polymorphisms (SNPs) that define the genetic background of the 35delG mutation over an interval of 98Kbp that includes the coding and flanking regions of GJB2. Two microsatellite markers, D13S175 and D13S141, were also analyzed in patients and controls. These data suggest that the 35delG mutation originated in north and northwest of Iran.

To use clinical and genetic analyses to determine the mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) segregating in two consanguineous Iranian families.Family study.Members of each family received otologic and audiometric examination for the type and extent of hearing loss. Linkage mapping using Affymetrix 50K GeneChips and short tandem repeat (STRP) analysis localized the hearing loss in both families to the DFNB3 locus. Direct sequencing of the MYO15A gene was completed on affected members of both families.Family L-3165 segregated a novel homozygous missense mutation (c.6371GA) that results in a p.R2124Q amino acid substitution in the myosin XVa protein, while family L-896 segregated a novel homozygous missense (c.6555CT) mutation resulting in a p.P2073S amino acid change.These are the first MYO15A mutations reported to cause DFNB3 sensorineural hearing loss in the Iranian population. Like other mutations located in the myosin tail homology 4 (MyTH4) domain, the p.R2124Q and p.P2073S mutations are predicted to disrupt the function of the myosin XVa protein, which is integral to the mechanosensory activity of hair cells in the inner ear.