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Recurrent miscarriages occur in about 5% of couples trying to conceive. In the past decade, the products of miscarriage have been studied using array comparative genomic hybridization (a-CGH). Within the last decade, an association has been proposed between miscarriages and single or multigenic changes, introducing the possibility of detecting other underlying genetic factors by whole exome sequencing (WES). We performed a-CGH on the products of miscarriage from 1625 Iranian women in consanguineous or non-consanguineous marriages. WES was carried out on DNA extracted from the products of miscarriage from 20 Iranian women in consanguineous marriages and with earlier normal genetic testing. Using a-CGH, a statistically significant difference was detected between the frequency of imbalances in related vs. unrelated couples ( P  < 0.001). WES positively identified relevant alterations in 11 genes in 65% of cases. In 45% of cases, we were able to classify these variants as pathogenic or likely pathogenic, according to the American College of Medical Genetics and Genomics guidelines, while in the remainder, the variants were classified as of unknown significance. To the best of our knowledge, our study is the first to employ WES on the products of miscarriage in consanguineous families with recurrent miscarriages regardless of the presence of fetal abnormalities. We propose that WES can be helpful in making a diagnosis of lethal disorders in consanguineous couples after prior genetic testing.

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.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, leading to 179 000 cancer-related deaths annually. ccRCC initiating cells (CICs) are thought to drive tumor initiation, growth, therapy resistance, and metastasis, yet their molecular characteristics remain poorly defined. This study aims to identify putative CICs and their essential genes using a cell marker-agnostic strategy. Methods We performed a comprehensive analysis of ccRCC transcriptomes at single-cell resolution, developed patient-derived xenograft (PDX) and 3D patient-derived organoids (PDO) models of ccRCC, and conducted functional examinations in these models to investigate our findings. Results Computational modeling of tumor formation using single-cell RNA velocity analysis of five primary and metastatic ccRCC-PDXs revealed a minor cell population as the origin of other tumor cells, representing putative CICs. Pathway and network analyses suggested that a core network of proteins, conventionally known to regulate mitosis, are highly active in CICs and may be essential for their function. These proteins were expressed in PDOs and PDX-derived spheroids established following a CIC enrichment protocol. Spheroid cells exhibited higher tumorigenicity and colony formation ability than parental tumor cells, as confirmed by in-vivo injection in nude mice and in-vitro colony formation assays. Successive in vivo passaging confirmed the self-renewal capacity of spheroid-derived tumors. Pharmacological blockade of candidate proteins elicited dose-dependent inhibitory effect on spheroid and colony formation, with in-vivo validation showing that blocking these proteins significantly delayed tumor growth and more efficiently prevented tumor formation in mice. These results highlight the importance of these proteins in the cancer-initiating abilities of malignant cells. Interestingly, our results suggest that the identified target proteins may elicit their CIC-related function independently from their mitosis regulatory roles. Conclusions We identified and validated essential proteins in RCC-CICs, supported by single-cell transcriptome data and RCC spheroids and PDX models. Targeting the vulnerabilities of RCC-CICs, given their role in tumor initiation, progression, and therapy resistance, offers significant potential for developing new anti-cancer therapies.

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.

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.

In a recent screening programme on hearing loss (HL), we examined 17 common autosomal recessive nonsyndromic hearing loss (ARNSHL) genes in every consanguineous Iranian family with ARNSHL that was referred to our centre. We first screened GJB2 mutations and then utilized a panel of three to four short tandem repeats to analyse rest of the loci. Once a homozygous by descent (HBD) pattern was observed for a given locus, direct sequencing was performed to identify the possible mutation. Families that did not show HBD pattern were screened through otologic sequence capture of pathogenic exons (OtoSCOPE) targeted sequencing panel. Using this strategy, we identied two novel mutations in the immunoglobuline-like domain-containing receptor 1 gene (ILDR1, MIM 609739): a 2-bp deletion, c.1217-18delTC and a substitution, c.305T>A, in consanguineous Iranian deaf families.