Rate Of Consanguineous Marriages Research Articles

Biallelic variants identified in 36 Pakistani families and trios with autism spectrum disorder

With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes (ARAP1, CDKL5, CSMD2, EFCAB12, EIF3H, GML, NEDD4, PDZD4, POLR3G, SLC35A2, TMEM214, TMEM232, TRANK1, TTC19, and ZNF292) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1, CSMD2, and NEDD4), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2. The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.

Genetic analysis of nephrogenic diabetes insipidus patients: A study on the Iranian population.

Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney. Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines. In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study. As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.

Consanguineous Marriages and the Perception of Wife-Beating Justification in Pakistan: An Application of Fairlie Decomposition Analysis.

Pakistan has a significant occurrence of both consanguineous marriages and intimate partner violence (IPV), which may be interlinked. The practice of consanguineous marriages could potentially influence women to rationalize and accept instances of IPV. Such attitudes perpetuate a culture of violence against women, creating difficulties for victims to reject or escape from it. Pakistan has high prevalence rate of consanguineous marriages and IPV. However, no research has been done to explain the difference in acceptance of IPV between women in consanguineous and non-consanguineous marriages. This study used Pakistan Demographic and Health Survey data and applied association tests, logistic regression, and the Fairlie decomposition analysis. The Fairlie decomposition helps us identify the relative contribution of different socioeconomic factors in the inequalities in IPV between the two types of marriages. Five dimensions of wife-beating justification are used as outcome variables. Age, education, and empowerment of women, husband education, woman witness parental violence, region, place of residence, and household wealth status are used as independent variables. The logistic regression results indicated that women in consanguineous marriages of younger age and who witnessed parental violence are more likely to justify wife-beating than those who belong to wealthy households and enjoy more empowerment. Compared to the Punjab province, women residing in Sindh and Baluchistan are less likely and in the Khyber Pakhtunkhwa province are more likely to justify wife-beating. The Fairlie decomposition analysis shows that household wealth status, woman education, and empowerment are the main contributors in explaining the gap between the wife-beating justification of the two groups. The IPV gap can be reduced up to 77% if the distribution of women in different wealth quantiles of the consanguineous marriage group is identical to the non-consanguineous marriage group. Furthermore, woman education level is the second highest contributor. Consanguineous marriages are a prevalent cultural practice in Pakistan and are associated with several negative health and social outcomes. Addressing this issue requires a sustained and comprehensive effort by the government, civil society, and international partners, with a particular focus on women from poor households with less education.

Identification of new variants in patients with mucopolysaccharidosis in consanguineous Iranian families.

Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.

Incidence, Phenotypes, and Genotypes of Neonatal Diabetes: A 16-Year Experience. The Rare Genetic Etiologies of Neonatal Diabetes Are Common in Sudan

Neonatal diabetes (ND) is a rare subtype of diabetes occurring in the first 6 months of life. High incidence has been reported among populations with high rates of consanguineous marriage. However, there is paucity of reported data from sub-Saharan African countries. We report the incidence, genotype, and phenotype of ND in a large cohort from Sudan and compare these findings to regional and international data. All infants with onset of diabetes in the first 6 months of life, attending one of the only two tertiary pediatric diabetes centers in Sudan, Gaafar Ibn Auf Pediatric Tertiary Hospital and Sudan Childhood Diabetes Center, during the period of January 2006 to December 2022 were included. Medical records were reviewed for demographic and clinical information. Genetic testing was performed for 48 patients by the Exeter Genomics laboratory in the UK and for one patient by the University of Cambridge, Metabolic Research Laboratories, UK. The estimated incidence was 4.8 per 100,000 live births. Forty-nine ND patients from 45 unrelated families were identified, and a genetic diagnosis was confirmed in 37 patients (75.5%) from 33 unrelated families. Consanguinity was reported in 34 families (75.6%). The commonest genetic cause for permanent neonatal diabetes was EIF2AK3 recessive variants causing Wolcott–Rallison syndrome (18.92%). Pathogenic variants in two recently identified genes, ZNF808 and NARS2, were found in three patients each (8.11%). Activating variants in KCNJ11 and ABCC8 were identified in four (10.81%) and two (5.41%) patients, respectively. Apart from hyperglycemia, the commonest clinical presentations included dehydration, failure to thrive, and diabetic ketoacidosis. ND in Sudan has a different pattern of etiologies compared to Western and Asian populations yet similar to some Arab countries with EIF2AK3 mutations being the commonest cause. Pathogenic variants in recently identified genes reflect the impact of genome sequencing on increasing the rate of genetic diagnosis.

Spectrum of genetic variants in bilateral sensorineural hearing loss.

Background: Hearing loss (HL) is an impairment of auditory function with identified genetic forms that can be syndromic (30%) or non-syndromic (70%). HL is genetically heterogeneous, with more than 1,000 variants across 150 causative genes identified to date. The genetic diagnostic rate varies significantly depending on the population being tested. Countries with a considerably high rate of consanguinity provide a unique resource for studying rare forms of recessive HL. In this study, we identified genetic variants associated with bilateral sensorineural HL (SNHL) using whole-exome sequencing (WES) in 11 families residing in the United Arab Emirates (UAE). Results: We established the molecular diagnosis in six probands, with six different pathogenic or likely pathogenic variants in the genes MYO15A, SLC26A4, and GJB2. One novel nonsense variant, MYO15A:p.Tyr1962Ter*, was identified in a homozygous state in one family, which has not been reported in any public database. SLC26A4 and GJB2 were found to be the most frequently associated genes in this study. In addition, six variants of uncertain significance (VUS) were detected in five probands in the genes CDH23, COL11A1, ADGRV1, NLRP3, and GDF6. In total, 12 variants were observed in eight genes. Among these variants, eight missense variants (66.7%), three nonsense variants (25.0%), and one frameshift (8.3%) were identified. The overall diagnostic rate of this study was 54.5%. Approximately 45.5% of the patients in this study came from consanguineous families. Conclusion: Understanding the genetic basis of HL provides insight for the clinical diagnosis of hearing impairment cases through the utilization of next-generation sequencing (NGS). Our findings contribute to the knowledge of the heterogeneous genetic profile of HL, especially in a population with a high rate of consanguineous marriage in the Arab population.

Consanguineous Marriage and Its Association With Genetic Disorders in Saudi Arabia: A Review.

Consanguineous marriages, where spouses are related by blood, have been a longstanding practice in human history. The primary medical concern with consanguineous marriages is the increased risk of genetic disorders. When closely related individuals reproduce, there is a higher probability that both parents carry the same genetic mutation. In Arab countries, especially Saudi Arabia, the rate of consanguineous marriage is high compared with Western European and Asian countries. This high rate is directly proportionate with elevated risk of genetic disorders, including congenital heart diseases, renal diseases, and rare blood disorders. Additionally, it was noted that the rate of negative postnatal outcomes is higher in consanguineous marriages compared with the general population. These observations indicate the necessity of tackling this area and highlighting the consequences of this practice. In this review, we aim to discuss the current evidence regarding the association between consanguineous marriages and genetic disorders in Saudi Arabia.

In silico analysis of mutation spectrum of Ehlers–Danlos, osteogenesis imperfecta, and cutis laxa overlapping phenotypes in Iranian population

BackgroundEhlers–Danlos syndrome (EDS), osteogenesis imperfecta (OI), and cutis laxa (CL) are three rare and heterogeneous connective tissue disorders. Patients with these syndromes have similar manifestations and unpredictable prognosis, making a misdiagnosis highly probable. Some of their subtypes are inherited in autosomal recessive patterns, so they are expected to be prevalent in populations like Iran, where consanguineous marriages are common. In the current work, a cohort of Iranian patients with overlapping phenotypes of the EDS/OI/CL and their mutation spectrum was defined. Based on this, in silico analysis was conducted to anticipate further probable genetic variations. Pathogenicity of EDS, OI, and CL variants in Iranian patients was evaluated using Web servers. A protein interaction network was created by String database and visualized using a Python-based library. The Iranome database was used to predict other genetic mutations in all reported genes of EDS, OI, and CL syndromes.ResultsIn the EDS/OI/CL overlap phenotype, 32 variants in 18 genes have been involved. At least 59% of patients were from families with consanguineous marriages. Interaction analysis showed that COL1A1, COL1A2, CRTAP, LEPRE1, PLOD1, and ADAMTS2 have the most significant impact within the protein network of EDS/OI/CL overlap phenotype. Analyzing the Iranome database revealed 46 variants of EDS, OI, and CL genes potentially disease causing.ConclusionThe overlapping phenotype of EDS, OI, and CL syndromes requires genetic testing (e.g., whole-exome sequencing) to reveal respective variants, which helps to diagnose more accurately and manage the disease more effectively. Particularly in populations with high rates of consanguineous marriages, such as Iran, genetic screening plays a crucial role in premarital and prenatal counseling to prevent the transmission of these rare connective tissue disorders.

Prevalence and socio-economic determinants of consanguineous marriages in Algeria according to Multiple Indicator Cluster Survey 2019 data (MICS6)

ABSTRACT Consanguineous marriage is still a customary social phenomenon in Arab-Muslim communities. The aim of this study was to estimate the prevalence of consanguineous marriages in the Algerian population and to identify the socio-economic determinants associated with the practice of this form of union. This is a descriptive cross-sectional study included data for 21141 ever-married women aged 15–49 years, from the MICS6 Algeria (Multiple Indicator Cluster Survey database), conducted in 2019. Using a logistic regression model, we assessed the influence of socio-economic and geographical determinants on the practice of consanguineous marriages. The prevalence of consanguinity was 23.0% (95% CI: 22.4–23.6). According to multivariable binary logistic regression analysis, low level of education, early age at marriage (15–19; 20–30 years), rural area of residence, all geographical regions except the north-western territorial programming space, economic activity, and the lowest wealth index were the main determinants that assist in the prevalence of high rates of consanguineous marriages in Algeria. Considering these explanatory variables could help national health policy decision-makers to create and implement national preventive action plans that are intended alter behaviors attitudes toward preference of consanguineous marriages and, thus, reduce the burden of genetic disorders or congenital abnormalities associated with consanguinity.

Thyroid Autoimmune Disease among Emirati Patients: A Retrospective Analysis of the Patients’ Characteristics

Background: Autoimmune thyroid disease (AITD) is a serious and treatable disease that could be associated with other autoimmune disorders. It is a common cause of hypothyroidism in adult females. The diagnosis is established by detecting serum antithyroid antibodies. The disease slowly progresses, and the treatment includes thyroid hormone replacement in cases of hypothyroidism. Objective: The aim of this study is to investigate the clinical presentation, laboratory findings, and comorbidity factors involved in autoimmune thyroid disease among Emirati citizens in the UAE. Methods: Medical records from Advanced Cure Diagnostic Centers were reviewed in a retrospective study over the period of four years from 2018 to 2022. The patients population included those who attended the Endocrinology Unit and others seen by the rest of the medical staff. Patients were considered to have AITD if they tested positive for thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), or both. The data collected was evaluated using descriptive analysis to provide a basic summary of the patients sample and dataset. Unpaired t-test was used to compare the mean value of elevated autoantibodies in males and females. Results: Of the 366 Emirati nationals who were tested for autoimmune thyroiditis, 220 (60%) had an abnormal result for TPOAb and/or TgAb. Among the 220 patients who had an abnormal result for TPOAb and/or TgAb, 188 (85.5%) were females, and 100 patients (45.5%) were in the age group between 31 and 40 years. 42% were in a euthyroid state and 42% presented with hypothyroidism. Only 7% presented with hyperthyroidism, 5% with subclinical hypothyroidism, and 2% with subclinical hyperthyroidism. An analysis of the comorbidity factors revealed that 142 (65%) patients with obesity, 82 (37%) with a family history of thyroid disease, 77 (35%) with hyperlipidemia, 14 (6%) with hypertension, and 11 (5%) with diabetes. Conclusion: This is the first publication intended to address AITD in Emirati citizens. Our findings concur with the international data regarding the prevalence among middle-aged females. Eighty-four percent of the positive patients either presented with no abnormality of their thyroid gland function or with hypothyroidism. With the alarming increase of obesity in the UAE, we found it to be the single most important and preventable comorbidity factor present in 65% of the studied population. This is followed by a family history of first-degree relatives with thyroid disease in 37% of the participants, due to the high rate of consanguineous marriages in the UAE.

High Prevalence of a Rare Bleeding Disorder: A Report from Glanzmann Thrombasthenia Registry of Al-Madinah, Saudi Arabia

Introduction Glanzmann thrombasthenia (GT) is a hereditary bleeding disorder caused by a defect or deficiency of platelet glycoprotein IIbIIIa. Though GT is considered a rare bleeding disorder, some countries in the Middle East report a high prevalence of GT. Aim Description of GT patients' prevalence, demographic, clinical, and genetic features in AlMadinah, Saudi Arabia. Methods This is a 20-year report from the AlMadinah GT registry in the Madinah Hemophilia Comprehensive Care Center. The registry has included all patients with a confirmed diagnosis of GT. To label a patient as GT, He must have absence or abnormal response in all agonists except ristocetin plus absence or reduced expression of platelet glycoprotein IIbIIIa on Flowcytometry. Next-generation sequencing is used to target sequencing for Molecular testing. The extracted data underwent an analysis process, where 136 GT patients were identified. Only 125 cases have complete data in records. Statistical analysis made via a statistical package of social sciences (SPSS) version 23. The research and ethical committee approved the study. Results The prevalence of GT among Saudis in AlMadinah, Saudi Arabia, based on the Saudi population in 2022, is 1:10,000. One hundred twenty-five GT patients were studied: 67 (54%) females and 58 (46%) males. The median age at the time of the report was 16.5 (10 days to 56 years). Ninety-nine (79%) patients have type 1 GT. Out of 108 (86%) whose Consanguinity status was recorded, 106 (98%) GT patients are products of consanguineous marriage. Seventy (65%) patients were products of first-degree cousin parents. Family history of GT was reported in 107 (86%) cases. Twenty-five families have more than one sibling (2-5) with GT. A single tripe has 50 members with GT. The median age at presentation is 2 years (7 days to 11 years). The most common symptoms are gum bleeds, Epistaxis, and Bruises. Eighteen (16%) patients suffered from a severe bleeding course (defined as bleeding continued for more than 3 days, drop in hemoglobin for more than 2 g / L from the baseline, or needed admission to the intensive care unit). Forty (35%) patients had a moderate course (bleeding requiring hospital admission and not filling the criteria for severe one). Fifty-seven (50%) patients had a mild clinical course (bleeding can be stopped at home). Eighteen (17%) patients had bleeding episodes more than once a month, 34 (32%) had six or fewer bleeds per year, and 57 (52%) patients had one bleeding episode per year. Menorrhagia affected 35 (86%) ladies and girls. Hormonal therapy has been used at least once in their lives to interfere with the menstrual cycle in 39 (95 %) patients. Twenty-eight pregnancies were reported, producing 24 babies (13 girls and 11 boys). A postpartum hemorrhage took place after 18 deliveries (75%). Mild to moderate pregnancy-related bleeding occurred in 7 pregnancies. Iron deficiency anemia was found in 66 (66%) patients out of 100 whose iron status was reported. Eighteen mutations have been identified: 15 mutations in the ITGA2B gene and 3 mutations in the ITGB3 gene (table 1). The mutation ITGA2B:exon13:c.1210+5G>A is a novel mutation found only in one tripe, where all 12 GT patients in this tripe carry this mutation. The mutation ITGA2B: exon20:c.1879-2A>G is the most frequent mutation affecting one tribe only, and all 42 GT patients who descend from this tribe carry this mutation. The second frequent mutation is ITGB3:exon13:c.2112delC, involving 28 GT patients. Though we could not find a correlation between genotype and phenotype, we noticed GT patients carrying mutations exon13:c.2112delC and exon13:c.1210+5G>A running a more severe clinical course compared to patients affected by the mutation ITGA2B: exon20:c.1879-2A>G. Anti-platelet antibodies have been detected in 11 (9%) patients, 2 of them during pregnancy. Apart from Menorrhagia, 10 out of 15 GT patients running severe clinical courses improved when they reached puberty. Conclusions GT is the commonest bleeding disorder in AlMadinah, Saudi Arabia, with a prevalence of 1:10,000. With a high rate of menorrhagia and IDA. The high rate of consanguineous marriage could be a reason for the high prevalence of GT.

Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran.

Hyperphenylalaninemia (HPA) is a metabolic disorder classified into phenylalanine-4-hydroxylase (PAH) and non-PAH deficiency. The latter is produced by mutations in genes involved in the tetrahydrobiopterin (BH4) biosynthesis pathway and DNAJC12 pathogenetic variants. The BH4 metabolism, including de novo biosynthesis involved genes (i.e., guanosine 5'-triphosphate cyclohydrolase I (GTPCH/GCH1), sepiapterin reductase (SR/SPR), 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS)), and two genes that play roles in cofactor regeneration pathway (i.e., dihydropteridine reductase (DHPR/QDPR) and pterin-4α-carbinolamine dehydratase (PCD/PCBD1)). The subsequent systemic hyperphenylalaninemia and monoamine neurotransmitter deficiency lead to neurological consequences. The high rate of consanguineous marriages in Iran substantially increases the incidence of BH4 deficiency. We utilized the Sanger sequencing technique in this study to investigate 14 Iranian patients with non-PAH deficiency. All affected subjects in this study had HPA and no mutation was detected in their PAH gene. We successfully identified six mutant alleles in BH4-deficiency-associated genes, including three novel mutations: one in QDPR, one in PTS, and one in the PCBD1 gene, thus giving a definite diagnosis to these patients. In this light, appropriate patient management may follow. The clinical effect of reported variants is essential for genetic counseling and prenatal diagnosis in the patients' families and significant for the improvement of precision medicine.

Clinical and Genetic Spectrum of Myotonia Congenita in Turkish Children.

Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle. The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort. Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated. Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment. The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.

Transfusion-Associated Graft-Versus-Host Disease in Adults.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but fatal complication of blood transfusion that usually develops two to 30 days following a blood transfusion giving rise to graft versus host disease (GVHD) clinical features that are consisting of fever, skin rash, jaundice, diarrhea, and pancytopenia. The disease is fulminant in most patients with a mortality rate of >90% of cases. The main aim of this review is to enhance awareness among medical practitioners about this fatal disease. Data were extracted manually from the main medical databases (Medline, Scopus, and Google Scholar) after the revision of selected articles and assessed for their contribution to the knowledge of TA-GVHD. TA-GVHD occurs when the viable donor T-cells in the blood or blood products attack the recipient's tissues which his/her immune system is incapable to destroy due to several reasons. The recipient's tissues that are usually involved in TA-GVHD include the liver, intestine, skin, lungs, and bone marrow. Any blood component either whole blood, packed red blood cells (RBCs), platelets, or fresh non-frozen plasma that contains viable T lymphocytes can cause TA-GVHD. Host immunodeficiency, transfusion of fresh blood, and partial human leukocyte antigen (HLA) matching between the donors and the recipients represent the major risk factors of TA-GVHD. Partial HLA matching includes immunocompetent recipients who receive blood from a first-degree relative also, seen in genetically homogenous populations because of high rates of consanguineous marriage. The diagnosis of TA-GVHD is mainly suspected based on clinical manifestations. However, a histopathological study of either skin or rectal biopsy is diagnostic. The treatment of TA-GVHD is generally not effective, unless the patient received emergency stem cell transplantation, while prevention via irradiation of blood or blood products represents the standard of care for this disease. In conclusion, medical practitioners should have a high index of suspicion for this disease. Moreover, future clinical trials targeting and comparing the outcomes of the different therapeutic options for TA-GVHD are required.

Detection of CYBA Gene Expression by Reverse Transcription PCR as a Diagnostic Tool for Autosomal Recessive Chronic Granulomatous Disease in a Sample of Egyptian Children

Abstract Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disease caused by functional impairment of the nicotinamide dinucleotide phosphate (NADPH) oxidase complex in neutrophilic granulocytes and monocytes, characterized by recurrent and severe infections, dysregulated inflammation, and autoimmunity. Approximately two-thirds of patients with CGD have defects in Cytochrome Bβ (CYBB), the X-linked gene encoding glycoprotein 91 phagocytic oxidase (gp91phox). Rarer autosomal recessive (AR) forms of CGD are caused by autosomal recessive mutations in CYBA genes encoding protein 22 phagocytic oxidase (p22phox). However, the incidence of autosomal recessive CGD can be higher than X-linked CGD in countries with high rates of consanguineous marriage. In the present study we aimed to diagnose the commonest AR-type of CGD by detection of CYBA gene expression using real time RT-PCR as a cheaper diagnostic method for CGD subtypes categorization among immunodeficient children. This case-control study was conducted on 15 children provisionally diagnosed as CGD patients with DHR stimulation index using phorbol myristate acetate (PMA) < 30% (Group I). The study also included 12 mothers and 8 fathers of the studied patients to detect the genetic mutations in carriers, if any (Group IIa and IIb respectively), and 14 apparently healthy children as a control group (Group III). We found that cases with a fold change of CYBA gene expression less than 0.6 were considered under-expressed. At this cut-off value, from our molecularly studied subjects 1 case and 2 mothers showed under-expression of CYBA gene. In conclusion, we could establish the diagnosis of AR-form of CGD, derives from defects in the CYBA gene, which encodes p22phox of the NADPH oxidase using real time RT-PCR, without the need to use complex and expensive methodologies such as northern blot, slot blot, or genomic DNA sequencing.

Perception of consanguineous marriage among the qatari population.

Hereditary blood diseases are widespread among the Arab population due to the high rates of consanguineous marriages; research regarding the perception of consanguineous marriage in some countries, such as Qatar, is extremely scarce. Therefore, this study aimed to investigate the prevalence of consanguineous marriage and assess the perception of consanguineous marriage among the Qatari population. A cross-sectional study used a self-administered questionnaire among 395 Qatari adults aged 18-35 who attended primary healthcare institutions in Qatar. A convenience sampling technique was used to select the study participants. An independent t-test was used to compare the significance of the mean between the two groups with positive and negative perceptions of consanguineous marriage. Categorical data were analyzed for association using the chi-square or Fisher's exact test. Finally, a multiple logistic regression analysis was conducted to determine the significant predictors of the positive perception of consanguineous marriage. A significant level was set at p < 0.05. Approximately 45% of the participants had a positive perception toward consanguineous marriage, and the most common reason stated by those participants was "habit and traditions." The prevalence of consanguineous marriage among married couples was 62.6%, and among those with consanguineous marriage, most were married to first cousins (81.7%). Moreover, compared to the participants with negative perceptions of consanguineous marriage, those with positive ones were significantly older, married, with lower educational levels and higher monthly income levels, did not hear about glucose-6-phosphate dehydrogenase (G6PD) deficiency, did not know what kinds of diseases are being screened in the premarital test, and were married to a relative. The prevalence of consanguineous marriage is high among the Qatari population, and this requires an immediate need for community-based campaigns to raise public awareness about the problem and its potential impact.

Mutational landscape of phenylketonuria in Iran.

To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to investigate the genetics bases of the PKU in different parts of the country. In this study, we have analysed and present an update of the mutational landscape of the PAH gene as well as the population genetics and frequencies of detected variants for each cohort. Published articles on PKU mutations in Iran were identified through a comprehensive PubMed, Google Scholar, Web of Science (ISI), SCOPUS, Elsevier, Wiley Online Library and SID literature search using the terms: "phenylketonuria", "hyperphenylalaninemia", and "PKU" in combination with "Iran", "Iranian population", "mutation analysis", and "Molecular genetics". Among the literature-related to genetics of PKU, 18 studies were on the PKU mutations. According to these studies, in different populations of Iran 1497 patients were included for mutation detection that resulted in detection of 129 different mutations. Results of genetic analysis of the different cohorts of Iranian PKU patients show that the most prevalent mutation in Iran is the pathogenic splice variant c.1066-11G > A, occurring in 19.54% of alleles in the cohort. Four other common mutations were p.Arg261Gln, p.Pro281Leu, c.168 + 5G > C and p.Arg243Ter (8.18%, 6.45%, 5.88% and 3.7%, respectively). One notable feature of the studied populations is its high rate of consanguineous marriages. Considering this feature, determining the prevalent PKU mutations could be advantageous for designing screening and diagnostic panels in Iran.

Reporting a novel growth hormone receptor gene variant in an Iranian consanguineous pedigree with Laron syndrome: a case report

BackgroundHuman growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors triggers downstream signaling pathways leading to the transcription of several genes, including insulin-like growth factor (IGF)-1. Pathogenic variants in the GHR gene can result in structural and functional defects in the GHR protein, leading to Laron Syndrome (LS) with the primary clinical manifestation of short stature. So far, around 100 GHR variants have been reported, mostly biallelic, as causing LS.Case presentationWe report on three siblings from an Iranian consanguineous family who presented with dwarfism. Whole-exome sequencing (WES) was performed on the proband, revealing a novel homozygous missense variant in the GHR gene (NM_000163.5; c.610 T > A, p.(Trp204Arg)) classified as a likely pathogenic variant according to the recommendation of the American College of Medical Genetics (ACMG). Co-segregation analysis was investigated using Sanger sequencing.ConclusionsTo date, approximately 400–500 LS cases with GHR biallelic variants, out of them 10 patients originating from Iran, have been described in the literature. Given the high rate of consanguineous marriages in the Iranian population, the frequency of LS is expected to be higher, which might be explained by undiagnosed cases. Early diagnosis of LS is very important, as treatment is available for this condition.

Clinical Profile and Bleeding Outcome of Pediatric Rare Bleeding Disorders: The Royal Hospital’s Experience, Oman

Introduction: Rare Bleeding Disorders (RBDs), a group of inherited coagulation factor deficiencies, are more common in areas with a high rate of consanguineous marriages. Data on the frequency and outcome of RBDs among children in Oman are limited. Aim: This study evaluated the clinical profile and bleeding outcomes of paediatric RBDs at the Royal Hospital, the largest referring centre in Oman, from 2010 to 2020. Methods: This retrospective descriptive cohort study includes all Omani children, less than 13 years of age, diagnosed with RBDs, and followed at the Royal Hospital. The patient’s data was retrieved from the electronic chart system. Results: Forty-one patients (24 males and 17 females) were included. Based on factor level at diagnosis, 34(83%) patients have factor VII deficiency, four (9.7%) patients have factor XIII deficiency, one (2.4%) patient has fibrinogen deficiency, and one patient (2.4%) has factor X deficiency. Four (9.4%) patients required blood transfusion for active bleeding, 15(36.6%) patients were treated on demand with tranexamic acid, and 3(7.3%) patients were on regular prophylaxis with tranexamic acid. The mean period of follow-up was 3.15 years. The majority (87.8%) of patients had no active bleeding, and only two (4.9%) patients developed severe bleeding. The mean annual bleeding rate outcome was 0.2, 0.5, and 7 for patients with FVII, FXIII, and FX, respectively. Conclusions: Omani children with rare bleeding disorders are commonly diagnosed incidentally. They usually do not require active treatment because their bleeding outcome is favourable.

Clinical, biochemical, and molecular characterization of mucopolysaccharidosis type III in 34 Egyptian patients.

Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.