High Rate Of Consanguinity Research Articles

Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort

PurposeThe genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from a 576 person well-phenotyped and highly consanguineous (16%) NDD cohort. MethodsWe used chromosomal microarray (CMA; N:247) and exome sequencing (ES; N:127) combined CMA, ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. ResultsGenetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared with those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. ConclusionThis study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.

Diagnostic challenges and outcome of fatty acid oxidation defects in a tertiary care center in Lebanon

BackgroundFatty acid oxidation defects are rare autosomal recessive disorders with variable clinical manifestations and outcome. Early detection by systematic neonatal screening may improve their prognosis. Long-term outcome studies of these disorders in the Middle East and North Africa region are limited. The purpose of this study is to report the diagnostic challenges and outcome of fatty acid oxidation defects in a major tertiary care center in Lebanon, a resource-constrained country in the Middle East.MethodsA retrospective review of charts of all fatty acid oxidation defects sequential patients diagnosed and followed at our center was conducted. Collected data included: parental consanguinity, age at diagnosis, clinical presentation, biochemical profile, confirmatory diagnosis, treatment and outcome. A genotype–phenotype correlation was also performed, when available.ResultsSeven types of fatty acid oxidation defects were identified in a total of 34 patients from 21 families. Most families (79%) were consanguineous (first-degree cousins). The majority were diagnosed when clinically symptomatic (78%), at various ages between 10 days and 19 years (average: 2 years). Follow-up duration spanned between 2 months and 15 years (average: 5 years). The remainder of the patients were detected while still asymptomatic by systematic neonatal screening (9%) or due to positive family history (9%). The most common defect was carnitine transporter deficiency (50%) with an exclusive cardiac presentation related to a founder variant c.981C > T, (p.Arg254*) in the SLC22A5 gene. Medium chain acyl-CoA dehydrogenase deficiency was found in 13% only, which could be explained by the absence of systematic neonatal screening. Rare gene variants were detected in very long chain and multiple acyl-CoA dehydrogenase deficiency. The worse prognosis was observed in very long chain acyl-CoA dehydrogenase deficiency. The overall survival at last follow-up reached 75% with a complete reversal of symptoms with treatment in most patients (63%), despite their late diagnosis.ConclusionsOur experience highlights the diagnostic challenges and outcome of fatty acid oxidation defects in a resource-constrained country with high consanguinity rates. Physicians’ awareness and systematic neonatal screening are key for diagnosis. Larger genotype–phenotype studies are still needed to understand the natural history of these rare diseases and possibly improve their outcome.

The prevalence of orofacial clefts in Qatar : a cross-sectional nationwide study

BackgroundCleft lip and palate are congenital craniofacial anomalies that significantly impact individuals and their families, both medically and psychosocially. The Qatari population has unique characteristics that are suggestive of a high prevalence of congenital anomalies: high consanguinity rate, large family size, advanced paternal age and high prevalence of certain genetic disorders. The lack of existing data concerning the epidemiology of cleft lip and/or palate in Qatar warrants a descriptive study addressing this topic.MethodsA retrospective nationwide hospital-based cross-sectional study conducted to determine the prevalence of orofacial clefts in Qatar from 2016 to 2021. Data were extracted from the corporation’s Cerner database and electronic health records. Information concerning the cleft’s characteristics, type, affected side, patient’s gender, presence of associated syndromes, nationality, and maternal age were collected.ResultsOut of the 147,727 live births, 148 had an orofacial cleft. The prevalence of cleft lip and/or palate was determined to be 1 per 1000 livebirths (95% CI: 0.85, 1.18). The prevalence of cleft lip was 0.18 (95% CI: 0.12, 0.27), cleft palate 0.39 (95% CI: 0.30, 0.51), and cleft lip and palate 0.43 (95% CI: 0.33, 0.55). Qataris had a prevalence of CL 0.25, CP 0.40, and CLP 0.56, compared to 0.16, 0.39, 0.39 for non-Qataris (p-value 0.186). Unilateral clefts predominated over bilateral (74.4% and 25.6%, respectively). Among the unilateral cases, 70.2% occurred on the left side. Most cases were isolated clefts, with only 10.2% having associated syndromes.ConclusionsThe prevalence of orofacial clefts in Qatar is consistent with the globally reported prevalence. Most cases were unilateral and on the left side. Associated syndromes were infrequent and more common with cleft palate alone. Intriguing patterns were revealed between Qatari nationals and non-Qatari residents, with specific subtypes of orofacial clefts showing higher prevalence among nationals.

A Rare Combination of Compound Heterozygous Mutations in the PAH Gene in Three Unrelated Consanguineous Iranian Families with Classical Phenylketonuria.

The PAH gene mutations have been linked to the development of phenylketonuria (PKU), which is recognized as the most common inborn metabolic disorder, and is caused by a deficiency in the phenylalanine hydroxylase (PAH) enzyme. The Iranian population, known for its diversity and high consanguinity, offers a valuable sample for studying autosomal recessive disorders. Our study investigated three unrelated families with PKU from Iran, utilizing clinical, laboratory, and computational approaches. We performed direct PCR sequencing for 13 exons of the PAH gene on three Iranian patients who were diagnosed with PKU. Then, Sanger sequencing confirmed the segregation of the mutations from parents to probands. Pathogenicity predictor tools, including ACMG, CADD, SIFT, Polyphen-2, and Mutation Taster, were utilized to analyze the identified genetic variants. The three-dimensional structure of the mutant forms of the protein was predicted. We also analyzed the protein-protein interactions of PAH using the STRING database. All three patients exhibited rare compound heterozygosity rearrangements in the PAH gene (NM_000277.3). These included three missense variants: [c.533A>G/c.1222C>T], [c.526C>T/c.1222C>T], and [c.533A> / c.526C>T]. This study adds to the body of evidence establishing the association between PAH mutations and the development of PKU. We speculated that the conjunction of a high consanguinity rate in populations such as Iran, coupled with the founder effect, can give rise to atypical genetic profiles, as observed in the rearrangement of compound heterozygosity in this study Moreover, our research underscores the significance of genetic testing in the precise diagnosis of individuals affected by inborn errors of metabolism.

Analysis of 14,392 whole genomes reveals 3.5% of Qataris carry medically actionable variants.

Arabic populations are underrepresented in large genome projects; therefore, the frequency of clinically actionable variants among Arabs is largely unknown. Here, we investigated genetic variation in 14,392 whole genomes from the Qatar Genome Program (QGP) across the list of 78 actionable genes (v3.1) determined by the American College of Medical Genetics and Genomics (ACMG). Variants were categorized into one of the following groups: (1) Pathogenic (P), (2) Likely pathogenic (LP), and (3) Rare variants of uncertain significance with evidence of pathogenicity. For the classification, we used variant databases, effect predictors, and the disease-relevant phenotypes available for the cohort. Data on cardiovascular disease, cancer, and hypercholesterolemia allowed us to assess the disease-relevant phenotype association of rare missense variants. We identified 248 distinct variants in 50 ACMG genes that fulfilled our criteria to be included in one of the three groups affecting 1036 genotype-positive participants of the QGP cohort. The most frequent variants were in TTN, followed by RYR1 and ATP7B. The prevalence of reportable secondary findings was 3.5%. A further 46 heterozygous variants in six genes with an autosomal recessive mode of inheritance were detected in 200 individuals, accounting for an additional 1.4%. Altogether, they affect 5% of the population. Due to the high consanguinity rate in the QGP cohort (28% in spouses and 60% in parents), P and LP variants both in genes with dominant and recessive inheritance are important for developing better treatment options and preventive strategies in Qatar and the Arabic population of the Middle East.

Frequency of Duffy, Kidd, Lewis, and Rh Blood Group Antigens and Phenotypes Among Donors in the Al-Ahsa Region, Saudi Arabia.

In Al-Ahsa, Saudi Arabia, the high consanguinity rates contribute to the prevalence of inherited hemoglobinopathies such as sickle cell disease and thalassemia, which frequently require blood transfusions. These transfusions carry the risk of alloimmunization, necessitating a precise blood component matching to mitigate health risks. Local antigen frequency data is vital for optimizing transfusion practices and enhancing the safety of these medical procedures for the Al-Ahsa population. This study investigated the distribution of Duffy, Kidd, Lewis, and Rh blood group antigens in 1,549 individuals from the region; comparing the frequencies with global data. Serological analyses revealed a high prevalence of the Fy(a+b-) and Jk(a+b+) phenotypes in the Duffy and Kidd blood groups, respectively, with Jk(a-b-) being notably scarce. The Lewis blood group exhibited a significant presence of Le(a-b+) and Le(a+b-) phenotypes, whereas Le(a+b+) was less common. In the Rh system, the D antigen was most prevalent, with other antigens following in descending order of frequency. The study underscores the regional variation in antigen frequencies, emphasizing the need for local blood banks to adapt their screening and matching practices to mitigate the risk of alloimmunization and enhance transfusion safety. These findings are pivotal for refining transfusion strategies and understanding the immunohematology landscape in Al-Ahsa.

Impact of Consanguinity and Familial Aggregation on Vitiligo Epidemiology in Saudi Arabia: A Case-Control Study.

Background Vitiligo, characterized by depigmented patches due to melanocyte loss, involves genetic, autoimmune, and environmental factors. Recent studies suggest a link between family history, consanguinity, and vitiligo prevalence, particularly in regions with prevalent consanguineous marriages. This study explored the relationship between consanguinity and familial vitiligo prevalence in Saudi Arabia. Methods A case-control study enrolled 792 participants from Saudi dermatology clinics (382 vitiligo cases, 408 controls). Family histories and consanguinity levels were assessed. Logistic regression analysis, adjusting for relevant variables, evaluated associations. Results Significant associations were found between vitiligo and both parental consanguinity and family history. Cases had higher consanguinity rates, with 246 out of 382 (64.4%), compared to controls, with 161 out of 408 (39.5%). A positive family history of vitiligo was more common in cases, with 184 out of 382 (48.2%)than in controls, with 90 out of 408 (22.1%). Logistic regression identified parental consanguinity and positive family history as significant risk factors for vitiligo, with adjusted odds ratios (aOR) of 2.39 and 2.92, respectively. Their synergistic effect notably amplified the risk (aOR = 7.58), indicating a complex genetic and familial influence on vitiligo in Saudi Arabia. Conclusions Consanguinity showed a significant association with vitiligo prevalence, highlighting genetic factors' role. Further genetic research is needed to identify specific mutations in vitiligo among consanguineous populations. Genetic counseling and awareness programs are crucial in regions with high consanguinity rates to mitigate vitiligo and other genetic disorders' risks.

HGG-28. THE IMPACT OF CMMRD IN HIGH-GRADE GLIOMA PATIENTS, A RETROSPECTIVE ANALYSIS OF 7 YEARS IN LMIC; AN IRRDC STUDY

Abstract BACKGROUND Constitutional mismatch repair (MMR) deficiency (CMMRD) is a genetic cancer predisposition syndrome presenting among children and young adults. This study is the first to evaluate CMMRD prevalence among high-grade glioma patients in Pakistan, a country with high consanguinity rates. METHODS We reviewed data of patients younger than 18 diagnosed with pediatric high-grade glioma, anaplastic astrocytoma, and diffuse midline glioma with CMMRD testing between 2016 and 2023. Tumor slides of all included cases were prepared and sent to Sick Kids Toronto to review the MMR protein stains via multi-gene panels. RESULTS Forty-five patients were identified (62.3% females); median age of 11. Headache (88.9%) was the most common symptom, followed by vomiting (60%) and seizures (37.8%); median duration of symptoms was two months. Histopathology revealed 73.3% pediatric high-grade glioma, 22.2% Anaplastic Astrocytoma, and 4.4% Diffuse Midline Glioma. Thirty-six patients (80%) had a cerebral tumor, 13.3%, and 6.7% had a posterior fossa and midline tumor, respectively. CMMRD was positive in 15 of 45 patients (33.3%). Eight patients (53.4%) had CMMRD with loss of PMS 2, two (13.3%) had loss of PMS 2 and MLH 1, two (13.3%) had loss of MSH 2, two (13.3%) had loss of MSH 6, and only one patient had loss of MSH 6 and MSH 2. Consanguinity correlated with CMMRD (P=0.045), but family history of malignancy was not significant (P=0.202). One-year overall survival of all patients, with a median follow-up of 4.8 months, was 44.4 %, whereas 1-year overall survival compared to CMMRD was 33.3%, with a median follow-up of 7.2 months (P=0.616) CONCLUSION We found high prevalence of CMMRD among pediatric high-grade glioma patients and patients with consanguinity. The findings of our study emphasize the importance of genetic testing and counseling. Timely accurate diagnosis is essential as decreased response to conventional treatment regimens may increase disease burden.

HGG-01. DURABLE RESPONSE TO IMMUNOTHERAPY IN AN ADOLESCENT PATEINT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY CMMRD AND SYNCHRONOUS THREE PRIMARY MALIGNANCIES

Abstract BACKGROUND Familial Cancer Syndrome FCS is of particular concern in Saudi Arabia due to the high rates of consanguinity. Constitutional mismatch repair deficiency Syndrome (CMMRD) is an autosomal recessive FCS with a wide spectrum of malignancies Caused by Biallelic germline mutations in one of 4 mismatch repair genes (MLH1, PMS2, MSH2, and MSH6). METHODS we report 13 yr. Saudi boy, previously healthy with multiple café-au-lait (CAL) macules, and Consanguineous parents with a positive family history of Malignancy. presented with progressive headache, vomiting, abdominal pain, weight loss, and microcytic anemia. MRI Brain showed a Large left hemispheric necrotic mass, MRI abdomen: Circumferential gastric body wall thickening Distal transverse colon intraluminal polypoid mass, and liver hypodense lesion. He had a Resection of the brain tumor and Upper GI endoscopy + colonoscopy with polypectomy: which showed an Ugly gastric ulcer, and multiple colonic polyps. RESULTS Brain tumor molecular pathology: Gliosarcoma WHO grade 4 with negative IHC expression in PMS2 protein, hypermutant tumor with somatic PMS2 ATRX, TP53, NFI, and PIK3R1 genes mutation. stomach biopsy confirmed invasive gastric adenocarcinoma and Colonic polyp biopsy: Tubulovillous adenoma. Genetic testing Detect pathogenic Biallelic germline PMS2 mutation. He received adjuvant focal Brain radiation therapy 59.4Gy/33 F concurrent with immunotherapy (PD-1) inhibitor Nivolumab. Follow-up Abdominal imaging showed excellent response to immunotherapy with no significant residual lesion. MRI of the brain showed surgical bed multi-cystic lesions with thick nodular enhancement suggestive either of radiation necrosis vs. progressions/pseudoprogression. repeated MRI confirmed further progression of the enhancing surgical cavity lesion which was unresectable. CTLA-4 Inhibitor ipilimumab was added to Nivolumab to optimize therapy. UpToDate our patient is clinically stable on Maintenance Nivolumab with no side effects. CONCLUSION Our case confirms immunotherapy’s efficacy for treating CMMRD-related cancers, which can improve survival while reducing toxicity from less effective conventional therapies.

Awareness of consanguineous marriage burden and willingness towards premarital genetic testing in Sudan: a national cross-sectional study.

Despite the widespread practice of consanguinity in Sudan, there is a lack of exploration into the community's awareness of its health implications on offspring and their overall attitude towards consanguineous unions. This study aimed to evaluate the community's awareness of the possible health adversities of consanguinity on children and assess the effect of knowledge level on the prevailing attitude towards this practice in Sudan. From August to December 2018, data were collected from adults aged 18 years and above in five provinces of Sudan regardless of their marital status. The analysis involved both descriptive and multivariate statistical techniques. This study revealed a consanguinity rate of 30.2%. Despite a high awareness level (73.7%) regarding the effects of consanguineous marriage on the health of the offspring, a moderately negative attitude towards this practice (63.9%) was observed. The discordance between the high consanguinity rate in the Sudanese population and the moderately negative attitude suggests a potential persistence of this practice in the future. Without the implementation of educational programs and the provision of genetic counselling services to consanguineous couples, the prevalence of consanguinity is likely to endure.

Closing the gap: an urgent need for newborn screening of organic acid disorders in developing countries

Organic acid disorders are rare inherited metabolic disorders of key metabolic pathways. For the identification of specific organic acids, investigation of urinary metabolites and genetic testing are required through newborn screening programmes. Delayed diagnosis leads to complications, such as cardiac attacks, respiratory problems, neuro-developmental disorders, intellectual disability, and even premature death. The burden of such inherited disorders is quite high in developing countries of South Asia due to high rate of consanguinity in the region. Unfortunately, such disorders are left untreated due to the lack of screening facilities in such countries. The current narrative review was planned to highlight the urgent need for closing this gap and implementing effective newborn screening programmes for organic acid disorders in developing countries. ---Continue

Consanguinité et son impact sur la santé et la dynamique du génome : Un exemple de la Tunisie

The genetic disease spectrum in Tunisia arises from the founder effect, genetic drift, selection, and consanguinity. The latter represents a deviation from panmixia, characterized by a non-random matrimonial choice that may be subject to several rules, such as socio-cultural, economic, or other factors. This shifts the genetic structure away from the Hardy-Weinberg equilibrium, increasing homozygous genotypes and decreasing heterozygotes, thus raising the frequency of autosomal recessive diseases. Similar to other Arab populations, Tunisia displays high consanguinity rates that vary geographically. Approximately 60% of reported diseases in Tunisia are autosomal recessive, with consanguinity possibly occurring in 80% of families for a specific disease. In inbred populations, consanguinity amplifies autosomal recessive disease risk, yet it does not influence autosomal dominant disease likelihood but rather impacts its phenotype. Consanguinity is also suggested to be a major factor in the homozygosity of deleterious variants leading to comorbid expression. At the genome level, inbred individuals inherit homozygous mutations and adjacent genomic regions known as runs of homozygosity (ROHs). Short ROHs indicate distant inbreeding, while long ROHs refer to recent inbreeding. ROHs are distributed rather irregularly across the genome, with certain short regions featuring an excess of ROH, known as ROH islands. In this review, we discuss consanguinity's impact on population health and genome dynamics, using Tunisia as a model.

Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience.

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8years (range, 3.0-16.0years) at clinical diagnosis and 9.0years (range, 4.8-21.0years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCү2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center

ObjectiveInfantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. MethodsThis study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. ResultsMost patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. ConclusionThis study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Congenital Adrenal Hyperplasia - A Comprehensive Review of Genetic Studies on 21-Hydroxylase Deficiency from India.

Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the CYP21A2 gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene CYP21A1P imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of CYP21A2 gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of CYP21A2 mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on CYP21A2 gene reported from India. The results of these studies insist the compelling need for large-scale CYP21A2 genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of CYP21A2 gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.

Genetic literacy among primary care physicians in a resource-constrained setting

BackgroundGenetic literacy among primary healthcare providers is crucial for appropriate patient care with the advances in genetic and genomic medicine. Studies from high-income countries highlight the lack of knowledge in genetics and the need to develop curricula for continuing professional development of non-geneticists. Scarce data is available from resource-constrained countries in Middle East and North Africa. Lebanon is a small country in this region characterized by high rates of consanguinity and genetic disorders like several surrounding countries, such as Jordan, Syria, and Turkey.MethodsThe primary aim of this study assessed the genetic literacy, self-perceived and actual knowledge as well as practices among primary care providers in Lebanon. The secondary aim identified their educational needs and proposed evidence-based continuing education programs. A cross-sectional survey-based study, using a self-administered questionnaire, was conducted targeting physicians from Family Medicine, Obstetrics and Gynecology, and Pediatrics. The questionnaire was divided into five sections: demographics, familiarity with genetic tests, self-reported and actual knowledge, genetic practices, and educational needs. Statistics were performed using SPSS v24. The Chi-square test was used for independent variables. Differences between mean scores were measured using paired sample t-tests for groups of two levels and one-way ANOVA for more than two. Multiple linear regression was used to study the variables associated with the knowledge score while controlling for other variables.ResultsThe survey included 123 physicians. They were mostly familiar with karyotype as first-tier genetic test. Although 38% perceived their knowledge as good, only 6% scored as such in knowledge assessment. A better knowledge score was observed in academic institutions as well as in urban settings (p<0.05). One third never ordered any genetic testing, mostly due to poor knowledge. Almost all (98%) were ready to attend continuing professional development sessions in genetics.ConclusionOur findings show the need to improve genetic literacy among healthcare frontliners, focusing on remote regions and nonacademic centers in Lebanon, a model for other resource-constrained country in the Middle East and North Africa region. This study advances recommendations for evidence-based genetic continuing education programs and highlighted the role of that the few genetic specialists can play in their successful implementation.

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.

Comparing between HLA-matched sibling donor allogenic HSCT and non-sibling matched related donor allogenic HSCT outcome in pediatric patients; single center retrospective study.

Extended family donor search other than siblings may yield an HLA matched donor in communities with high rate of consanguinity. The outcome of patients who are transplanted from non-sibling matched related donors (NS-MRD) including engraftment and graft versus host disease (GVHD) are scarce in comparison with matched sibling donor (MSD). We retrospectively reviewed the outcome of all our pediatric hematopoietic stem cell transplantation (HSCT) patients who had non-sibling matched related donor and controlled them with matched sibling donor HSCT (based on age, indication of HSCT, conditioning regimen, GVHD prophylaxis, serotherapy, stem cell source and cytomegalovirus status). A total of 76 patients were reviewed during study period. Thirty patients (39.5%) in NS-MRD arm and 46 patients in MSD (60.5%) were identified after matching in age, disease, and conditioning regimens. All patients had similar approach including stem cell source and GVHD prophylaxis (CNI + 2nd agent). Out of the NS-MRD group, 18 patients (59%) had one of their parents as a donor and the rest as second degree relatives. Both groups were equally distributed and were homogeneous. Both groups had no statistically significant difference in outcome including engraftment, GVHD and Chimerism tests results. GVHD was seen in (13%) NS-MRD patients compared to (11%) in MSD patients. All patients remain alive with median follow up of 1249 days (431-3525). This study showed no significant difference in allogenic HSCT outcomes between matched sibling donors and non-sibling matched related donors and support using the same management approach in terms of conditioning therapy, GVHD prophylaxis, and serotherapy only if indicated.

Apparition of germline mutation c.1395-1397del of MUTYH in Algerian consanguineous family with colorectal cancer

MUTYH is a glycosylase that removes adenine opposite 8-oxoguanine (OG) during base-excision repair of DNA. Variants of MUTYH defective in functional activity lead to MUTYH-associated polyposis (MAP), autosomal recessive predisposition to colorectal cancer (CRC). MAP combines clinical features with other hereditary CRC syndromes, and exhibits phenotypic overlap, particularly with Lynch syndrome (LS). To determine the impact of MUTYH mutations in colorectal adenomas and cancer susceptibility, this prospective objective screens the MUTYH gene in seventeen Eastern Algerian families with clinically suspected LS but without mismatch repair (MMR) mutations. Methods: We examined the presence of the mutations in the probands and their relatives using direct sequencing of the entire coding region of the MUTYH gene. Results: The biallelic and monoallelic pathogenic MUTYH mutations, c.1395_1397del, were discovered in a consanguineous family with CRC and gastric cancer as a novel finding in our Eastern Algerian population. Conclusion: High rates of consanguinity in Algerian population increase the risk of CRC caused by biallelic mutations in the MUTYH gene. In our families, the LS and MAP phenotypes might coexist.