HFE and Non-HFE Hereditary Hemochromatosis Based on Screening of 854 Individuals: 12 Years of an Iranian Experience.

Introduction: The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as "suspected cases of HH," to a diagnostic laboratory in Iran over a 12-year period. Materials and Methods: From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of HFE exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the HFE, TFR2, and FPN1(SLC40A1) genes and 733 cases were screened using this method. Results: From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for HFE:C282Y and five homozygotes for TFR2:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other HFE variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). Conclusion: This study showed that the spectrum of genetic variants of HH in the Iranian population includes HFE and TFR2 variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue.

Genetic Analysis of 27 Y-STR Haplotypes in 11 Iranian Ethnic Groups.

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.

The First Iranian Case of Unstable Hemoglobin Santa Ana.

In this report, we describe a 6-year-old girl with a medical history of pallor, mild icterus, anemia, blood transfusion and abnormal hemoglobin variant analysis on capillary electrophoresis. She was referred for further analysis. DNA sequencing of the proband revealed a de novo mutation in Codon 88 (CTG > CCG) of the ß-globin gene (HBB: c.266T > C) in a heterozygous state compatible with hemoglobin Santa Ana, an unstable hemoglobin. This is the first case of Hb Santa Ana from Iran associated with moderate to severe anemia who underwent splenectomy with clinical improvement.

Contribution of genetic variants in the development of familial premature coronary artery disease in a cohort of cardiac patients.

Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one-third of patients with CAD have a positive family history, and individuals with such history are at ~1.5-fold increased risk of CAD in their lifespans. Accordingly, the long-recognized familial clustering of CAD is a strong risk factor for this disease. Our study aimed to identify candidate genetic variants contributing to CAD by studying a cohort of 60 large Iranian families with at least two members in different generations afflicted with premature CAD (PCAD), defined as established disease at ≤45 years in men and ≤55 years in women. Exome sequencing was performed for a subset of the affected individuals, followed by prioritization and Sanger sequencing of candidate variants in all available family members. Subsequently, apparently healthy carriers of potential risk variants underwent coronary computed tomography angiography (CCTA), followed by co-segregation analysis of the combined data. Putative causal variants were identified in seven genes, ABCG8, CD36, CYP27A1, PIK3C2G, RASSF9, RYR2, and ZFYVE21, co-segregating with familial PCAD in seven unrelated families. Among these, PIK3C2G, RASSF9, and ZFYVE21 are novel candidate CAD susceptibility genes. Our findings indicate that rare variants in genes identified in this study are involved in CAD development.

Identification of a Novel Variant in CC2D1A Gene Linked to Autosomal Recessive Intellectual Disability 3 in an Iranian Family and Investigating the Structure and Pleiotropic Effects of this Gene.

Objectives: Intellectual disability (ID) represents a significant health challenge due to its diverse and intricate nature. A multitude of genes play a role in brain development and function, with defects in these genes potentially leading to ID. Considering that many of these genes have yet to be identified, and those identified have only been found in a small number of patients, no complete description of the phenotype created by these genes is available. CC2D1A is one of the genes whose loss-of-function mutation leads to a rare form of non-syndromic ID-3(OMIM*610055), and four pathogenic variants have been reported in this gene so far. Materials & Methods: n the current study, two affected females were included with an initial diagnosis of ID who were from an Iranian family with consanguineous marriage. Whole-exome sequencing was used to identify the probable genetic defects. The Genotypic and phenotypic characteristics of the patients were compared with a mutation in the CC2D1A gene, and then the structure of the gene and its reported variants were investigated. Results: The patients carried a novel homozygous splicing variant (NM_017721, c.1641+1G>A) in intron 14, which is pathogenic according to the ACMG guideline. Loss-of-function mutations in CC2D1A have severe phenotypic consequences such as ID, autism spectrum disorder (ASD), and seizures. However, missense mutations lead to ASD with or without ID, and in some patients, they cause ciliopathy. Conclusion: This study reports the fifth novel, probably pathogenic variant in the CC2D1A gene. Comparing the clinical and molecular genetic features of the patients with loss-of-function mutation helped to describe the phenotype caused by this gene more precisely. Investigating the CC2D1A gene's mutations and structure revealed that it performs multiple functions. The DM14 domain appears more pivotal in triggering severe clinical symptoms, including ID, than the C2 domain.

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population.

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance.

Introduction: An insufficient functional beta cell mass is a core pathological hallmark of type 2 diabetes (T2D). Despite the availability of several effective pharmaceuticals for diabetes management, there is an urgent need for novel medications to protect pancreatic beta cells under diabetic conditions. Integrative organ cross-communication controls the energy balance and glucose homeostasis. The liver and pancreatic islets have dynamic cross-communications where the liver can trigger a compensatory beta cell mass expansion and enhanced hormonal secretion in insulin-resistant conditions. However, the indispensable element(s) that foster beta cell proliferation and insulin secretion have yet to be completely identified. Exosomes are important extracellular vehicles (EVs) released by most cell types that transfer biological signal(s), including metabolic messengers such as miRNA and peptides, between cells and organs. Methods: We investigated whether beta cells can take up liver-derived exosomes and examined their impact on beta cell functional genes and insulin expression. Exosomes isolated from human liver HepG2 cells were characterized using various methods, including Transmission Electron Microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis of exosomal markers. Exosome labeling and cell uptake were assessed using CM-Dil dye. The effect of liver cell-derived exosomes on Min6 beta cells was determined through gene expression analyses of beta cell markers and insulin using qPCR, as well as Akt signaling using Western blotting. Results: Treatment of Min6 beta cells with exosomes isolated from human liver HepG2 cells treated with insulin receptor antagonist S961 significantly increased the expression of beta cell markers Pdx1, NeuroD1, and Ins1 compared to the exosomes isolated from untreated cells. In line with this, the activity of AKT kinase, an integral component of the insulin receptor pathway, is elevated in pancreatic beta cells, as represented by an increase in AKT's downstream substrate, FoxO1 phosphorylation. Discussions: This study suggests that liver-derived exosomes may carry a specific molecular cargo that can affect insulin expression in pancreatic beta cells, ultimately affecting glucose homeostasis.

The Spectrum of HBB Mutations among 2315 Beta Thalassemia Patients of a Reference Clinic in Tehran-Iran.

Beta Thalassemia is the most prevalent and well-studied single gene disorder in Iran. Here, we investigated the spectrum of HBB gene mutations, identified among 2315 patients, referred to a reference thalassemia clinic in Tehran, on the basis of suspicion to thalassemia major or intermedia. The patients were homozygous or compound heterozygous for HBB mutations, and were referred from various Iranian provinces, during 15 years (2001- 2016). The HBB mutations were classified based on their frequency, and the result was compared to a meta-analysis of 14,293 beta thalassemia cases in the Iranian population, within the same time period. The mutation spectrum in this study contained 43 HBB mutations, compared to the 90, presented by the meta-analysis. Similar to the meta-analysis, IVSII-1 (G > A) and IVSI-5 (G > C) were the most common mutations in this study. These two comprised 62.40% of the total HBB mutant alleles in the studied population, comparable to 51.92% of that in the meta-analysis. IVSII-1 (G > A) and IVSI-5 (G > C), followed by 17 other mutations that had frequencies ranging from 0.15% to 5.44%, were among the 20 common HBB mutations in Iran and neighboring countries, according to the meta-analysis. This study provided further evidence to support the spectrum of the most common HBB mutations in the Iranian population.

An Extended Iranian Family with Autosomal Dominant Non-syndromic Hearing Loss Associated with A Nonsense Mutation in the DIAPH1 Gene.

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.

Identification of a homozygous frameshift mutation in the FGF3 gene in a consanguineous Iranian family: First report of labyrinthine aplasia, microtia, and microdontia syndrome in Iran and literature review.

BACKGROUND: To date, over 400 syndromes with hearing impairment have been identified which altogether constitute almost 30% of hereditary hearing loss (HL) cases around the globe. Manifested as complete or partial labyrinthine aplasia (severe malformations of the inner ear structure), type I microtia (smaller outer ear with shortened auricles), and microdontia (small and widely spaced teeth), labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome (OMIM 610706) is an extremely rare autosomal recessive condition caused by bi-allelic mutations in the FGF3 gene. METHODS: Using the whole-exome sequencing (WES) data of the proband, we analyzed a consanguineous Iranian family with three affected members presenting with congenital bilateral HL, type I microtia, and microdontia. RESULTS: We discovered the homozygous deletion c.45delC in the first exon of the FGF3 gene, overlapping a 38.72 Mb homozygosity region in chromosome 11. Further investigations using Sanger sequencing revealed that this variant co-segregated with the phenotype observed in the family. CONCLUSION: Here, we report the first identified case of LAMM syndrome in Iran, and by identifying a frameshift variant in the first exon of the FGF3 gene, our result will help better clarify the phenotype-genotype relation of LAMM syndrome.

The prevalence and phenotypic range associated with biallelic PKDCC variants.

PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.

BACKGROUND: The role of biallelic variants in the NRCAM gene underlying a neurodevelopmental disorder has been defined recently. The phenotype is mainly recognized by varying severity of global developmental delay/intellectual disability, hypotonia, spasticity, and peripheral neuropathy. METHODS: Here, we describe a patient with an initial diagnosis of motor-predominant axonal polyneuropathy or a form of distal SMA. Whole-exome sequencing (WES), in parallel with WES-based CNV detection and assessment of homozygosity runs, was performed to identify this patient's possible genetic cause. RESULTS: Whole exome sequencing revealed a homozygous variant, c.73C > T (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of phenotypes compared to NRCAM-related disorder. He presented only motor-predominant axonal polyneuropathy with no other signs of central nervous system involvement. CONCLUSIONS: This study is the second report of an association between biallelic NRCAM gene variants and a Mendelian disorder. The obtained clinical data, together with the molecular findings in this patient, expands the clinical and molecular spectrum of NRCAM-related disorder and highlights its phenotypic complexity. Although patients with loss of function variants in this gene have previously presented severe clinical features, we show that type of the pathogenic variant does not necessarily determine the severity of this phenotype.

A biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly.

Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule-binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family-based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (-4.3 SD at birth, -6.1 SD by 42 months), pachygyria, and global developmental delay from a consanguineous Turkish kindred. Droplet digital PCR (ddPCR) confirmed mutant mRNA expression in fibroblasts. In silico prediction of the translation of mutant PPP1R35 is expected to be elongated by 18 amino acids before encountering a downstream stop codon. This complex indel allele is absent in public databases (ClinVar, gnomAD, ARIC, 1000 genomes) and our in-house database of 14,000+ exomes including 1800+ Turkish exomes supporting predicted pathogenicity. Comprehensive literature searches for PPP1R35 variants yielded two probands affected with severe microcephaly (-15 SD and -12 SD) with the same homozygous indel from a single, consanguineous, Iranian family from a cohort of 404 predominantly Iranian families. The lack of heterozygous cases in two large cohorts representative of the genetic background of these two families decreased our suspicion of a founder allele and supports the contention of a recurrent mutation. We propose two potential secondary structure mutagenesis models for the origin of this variant allele mediated by hairpin formation between complementary GC rich segments flanking the stop codon via secondary structure mutagenesis.

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Expanding the Molecular Spectrum of HK1-Related Charcot-Marie-Tooth Disease, Type 4G; the First Report in Iran.

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.

Five patients with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME): a novel pathogenic variant, treatment and review of the literature.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments.

DNA Banking to Assess Genetic Influences on Schizophrenia.

Background: Schizophrenia is among the most prevalent psychiatric disorders globally, with a lifetime prevalence rate of 0.3% to 0.7%, characterized by the heterogeneous presence of positive, negative, and cognitive symptoms that affect all aspects of mental activity. We aimed to describe the genetics of schizophrenia to widening our understanding of the inheritance of this illness. Methods: This quasi-experimental study was conducted in Razi psychiatric hospital in Tehran province, Iran. Recruitment of the study samples was conducted in Tehran, Iran, among patients with schizophrenia and their families. For this purpose, individuals with schizophrenia in 40 families with at least 1 to 2 affected members were identified and selected based on a clinical interview conducted by a psychiatrist and according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. The clinical and paraclinical data, drug and substance usage, and medical treatments were collected through a standardized clinical questionnaire. Besides, the Global Assessment Scale and the Positive and Negative Syndrome Scale were completed for all study participants. Results: A total of 22 families had a negative family history, and 1 affected member and the rest of the studied families had a positive family history and at least 2 affected members. In addition, genealogical data (family tree) and lymphoblastic cell categories were developed to examine genes, and subsequent research results will be reported in the future. Conclusion: As the research continues, the approach to sampling must be modified to ensure that the deoxyribonucleic acid bank is as extensively representative as possible of all schizophrenia cases.

The Effect of Xmn -1 Polymorphism and Coinheritance of Alpha Mutations on Age at First Blood Transfusion in Iranian Patients with Homozygote IVSI-5 Mutation.

Background : Thalassemia syndromes are the most prevalent hereditary hemoglobinopathies in the world. Iran is located on the thalassemia belt.  In this study, the effect of Xmn -1 polymorphism and coinheritance of alpha mutations on age at first transfusion and also transfusion interval in Iranian thalassemic patients with homozygous IVSI-5 mutation were assessed. Materials and Methods : In this retrospective cross-sectional study 154 transfusion dependent thalassemia (TDT) patients (140 patients with ß-thalassemia major and 14 cases with ß-thalassemia intermedia) who were homozygote of IVSI-5 mutation have been participated. Blood samples were collected from participants using EDTA containers for genomic DNA analysis. DNA extraction and amplification-refractory mutation to determine the Xmn -1 polymorphism were performed. Multiplex PCR was performed to identify alpha globin deletions.  Results: The mean age of participants was 29±7, 58 of them were male and 96 were female. A significant relation between presence of Xmn -1 polymorphism and age at receiving first transfusion was detected. Coinheritance of alpha thalassemia mutation does not have significant effect on age at first transfusion or transfusion interval. Conclusion : Presence of Xmn -1 polymorphism can delay the onset of transfusion in patients with homozygote IVSI-5 mutation.

Erratum: Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3.

[This corrects the article DOI: 10.1016/j.xhgg.2021.100024.].