Consanguineous Population Research Articles

The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families

Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.

Non-invasive prenatal testing for autosomal recessive disorders: A new promising approach.

Background: In pregnant women at risk of autosomal recessive (AR) disorders, prenatal diagnosis of AR disorders primarily involves invasive procedures, such as chorionic villus sampling and amniocentesis. Methods: We collected blood samples from four pregnant women in their first trimester who presented a risk of having a child with an AR disorder. Cell-free DNA (cfDNA) was extracted, amplified, and double-purified to reduce maternal DNA interference. Additionally, whole-genome amplification was performed for traces of residual purified cfDNA for utilization in subsequent applications. Results: Based on our findings, we detected the fetal status with the family corresponding different genes, i.e., LZTR1, DVL2, HBB, RNASEH2B, and MYO7A, as homozygous affected, wild-type, and heterozygous carriers, respectively. Results were subsequently confirmed by prenatal amniocentesis. The results of AmpFLSTR™ Identifiler™ presented a distinct profile from the corresponding mother profile, thereby corroborating the result reflecting the genetic material of the fetus. Conclusion: Herein, we detected AR disease mutations in the first trimester of pregnancy while surmounting limitations associated with maternal genetic material interference. Importantly, such detection strategies would allow the screening of pregnant women for common AR diseases, especially in highly consanguineous marriage populations. This technique would open avenues for the early detection and prevention of recessive diseases among the population.

RF24 | PSUN127 Congenital Leptin Deficiency: Metabolic, Reproductive, and Psychological Impacts of Therapy

Abstract Background Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Monogenic obesity disorders, including CLD, have been reported to be prevalent among children with severe obesity in a consanguineous Pakistani population. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of the first cases of CLD identified in the United States, sisters of Pakistani origin with a family history of consanguinity. This report provides follow-up after 18 months of metreleptin therapy in an observational research protocol. Clinical Case Two sisters ages 18 yrs (A; BMI 45.2 kg/m2) and 20 yrs (B; 45.0 kg/m2) were referred for evaluation of obesity. Both had hyperphagia and excessive weight gain by age 3 months. They had been treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years and was treated with metformin and liraglutide with suboptimal glycemic control (HbA1C 9.3%). At the time of their initial evaluation, serum leptin levels were undetectable. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. Treatment was initiated with metreleptin 5 mg daily SC in Sister A and 3.75 mg SC daily, increasing to 5 mg daily at Week 8 in Sister B. Both remained on therapy throughout the 18 month observational trial without serious adverse effects or clinical evidence of neutralizing antibodies. At study end, both had substantial weight loss (Sister A: 45.3 kg or 32.8% of initial weight, Sister B: 39.1 kg or 33.1% of initial weight). Clinically significant improvements in related parameters were observed, including percent body fat (Sister A: -13%, Sister B: -18%), HOMA2-IR (A: -83%, B: -80%), ALT (A: -90%, B: -91%), triglycerides (A: -47%, B: -26%), hsCRP (A: -80%, B: -84%), FGF-21 (A: -81%, B: -67%), and adiponectin (A: +42%, B: +37%). In both sisters, hepatic steatosis improved and bone mineral density increased (A: +0.7 SD, B: +0.6 SD). At study end, Sister A's HbA1C was 5.4% off medication. Spontaneous regular menses resumed after 3 months of therapy in Sister A and four months in Sister B. Improvements were observed in mood, self-esteem, physical function, energy, quality of life, dietary disinhibition, and perceived hunger, measured by validated questionnaires. Conclusion Metrelepin produced significant improvements in weight, metabolic profiles, hepatic steatosis, reproductive function, mood and quality of life in our patients. Given the efficacy of metreleptin therapy, screening for CLD should be undertaken for any patient presenting with hyperphagia and early onset of obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:24 p.m. - 1:29 p.m.

Characterization of Arabian Peninsula whole exomes: Contributing to the catalogue of human diversity

The cataloging of human genomic variation is a challenging task given the size and diversity of the global human population. Several geographic regions remain under-characterized, such as the Arabian Peninsula (AP), which is unique in being at the cross-roads between Africa, Europe and Asia, and hence is a continuous hot-spot for admixture, counteracted by the worldwide highest levels of consanguinity. We conducted whole exome sequencing enriched for untranslated regions (WES+ UTRs) on 90 Arabians, and identified a considerable amount of new variants (∼17,000 out of ∼145,000). By applying pathogenic predicting tools, we demonstrated that AP WES have a high burden in potentially deleterious variants, especially in nonsynonymous and UTR variants, and that these are located in genes associated with neurologic diseases and congenital malformations. This burden was significantly and positively correlated with the consanguinity level. These results testify the importance of surveying consanguineous populations where pathogenic variants are not efficiently eliminated by genetic drift.

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS.Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next-generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations.A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1.Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.

Missense Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract.

The use of next-generation sequencing (NGS) has helped in identifying many genes that cause congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT, and its association with autosomal recessively inherited genes is expanding. Highly consanguineous populations can impact the detection of recessively inherited genes. Here, we report two families harboring homozygous missense variants in recently described genes, NPNT and GFRA1. Two consanguineous families with neonatal death due to CAKUT were investigated. Fetal ultrasound of probands identified BRA in the first family and severe renal cystic dysplasia in the second family. Exome sequencing coupled with homozygosity mapping was performed, and Sanger sequencing was used to confirm segregation of alleles in both families. In the first family with BRA, we identified a homozygous missense variant in GFRA1: c.362A>G; p.(Tyr121Cys), which is predicted to damage the protein structure. In the second family with renal cystic dysplasia, we identified a homozygous missense variant in NPNT: c.56C>G; p.(Ala19Gly), which is predicted to disrupt the signal peptide site. We report two Saudi Arabian consanguineous families with CAKUT phenotypes that included renal agenesis caused by missense variants in GFRA1 and NPNT, confirming the role of these two genes in human kidney development.

Rare variant analysis of obesity-associated genes in young adults with severe obesity from a consanguineous population of Pakistan

Rare variant analysis of obesity-associated genes in young adults with severe obesity from a consanguineous population of Pakistan

Mutation Rate Analysis of RM Y-STRs in Deep-Rooted Multi-Generational Punjabi Pedigrees from Pakistan.

Y chromosome short tandem repeat polymorphisms (Y-STRs) are important in many areas of human genetics. Y chromosomal STRs, being normally utilized in the field of forensics, exhibit low haplotype diversity in consanguineous populations and fail to discriminate among male relatives from the same pedigree. Rapidly mutating Y-STRs (RM Y-STRs) have received much attention in the past decade. These 13 RM Y-STRs have high mutation rates (>10−2) and have considerably higher haplotype diversity and discrimination capacity than conventionally used Y-STRs, showing remarkable power when it comes to differentiation in paternal lineages in endogamous populations. Previously, we analyzed two to four generations of 99 pedigrees with 1568 pairs of men covering one to six meioses from all over Pakistan and 216 male relatives from 18 deep-rooted endogamous Sindhi pedigrees covering one to seven meioses. Here, we present 861 pairs of men from 62 endogamous pedigrees covering one to six meioses from the Punjabi population of Punjab, Pakistan. Mutations were frequently observed at DYF399 and DYF403, while no mutation was observed at DYS526a/b. The rate of differentiation ranged from 29.70% (first meiosis) to 80.95% (fifth meiosis), while overall (first to sixth meiosis) differentiation was 59.46%. Combining previously published data with newly generated data, the overall differentiation rate was 38.79% based on 5176 pairs of men related by 1–20 meioses, while Yfiler differentiation was 9.24% based on 3864 pairs. Using father–son pair data from the present and previous studies, we also provide updated RM Y-STR mutation rates.

Prevalence and profile of inherited metabolic disorders in Libya: single center experience

Background: Inherited Metabolic Disorders (IMDs) are collectively common, particularly in a highly consanguineous population. Early diagnosis and prompt treatment are crucial to prevent permanent damage to the central nervous system as well as other devastating irreparable damage and even death. This study was conducted to determine the prevalence of IMDs in children seen at the Pediatric Department, Faculty of Medicine, Misurata University, Libya. Methods: In this cross-sectional study, medical records of all patients with IMDs over 6 years’ experience were studied. Related information to age, gender, consanguinity, family history, disorder type, diagnostic criteria and disease outcomes were extracted and analyzed. RESULTS: 57 patients were included in this study; 39 patients were male (68.4%) and 18 patients were females (31.6%) [M: F= 2.17:1] and the mean age at diagnosis was 1.9 years. Consanguinity was reported in 47 patients (82.5%), with family history being found in 71.9% of patients. 16 patients have mucopolysaccharidosis (28.1%), 11 patients have Glycogen storage diseases (19.3%),4 Nieman pick disease (7%), while the rest constitute the small molecular weight disease. Conclusion: IMDs are an up growing field of medicine, initial baseline diagnostic tools could take place in any specialized center and newborn screening should be established in Libya because of the high prevalence of IMDs. The lysosomal storage diseases are particularly common; however, many were still undiagnosed.

Patterns and distribution of de novo mutations in multiplex Middle Eastern families

While de novo mutations (DNMs) are key to genetic diversity, they are also responsible for a high number of rare disorders. To date, no study has systematically examined the rate and distribution of DNMs in multiplex families in highly consanguineous populations. Leveraging WGS profiles of 645 individuals in 146 families, we implemented a combinatorial approach using 3 complementary tools for DNM discovery in 353 unique trio combinations. We found a total of 27,168 DNMs (median: 70 single-nucleotide and 6 insertion-deletions per individual). Phasing revealed around 80% of DNMs were paternal in origin. Notably, using whole-genome methylation data of spermatogonial stem cells, these DNMs were significantly more likely to occur at highly methylated CpGs (OR: 2.03; p value = 6.62 × 10−11). We then examined the effects of consanguinity and ethnicity on DNMs, and found that consanguinity does not seem to correlate with DNM rate, and special attention has to be considered while measuring such a correlation. Additionally, we found that Middle-Eastern families with Arab ancestry had fewer DNMs than African families, although not significant (p value = 0.16). Finally, for families with diseased probands, we examined the difference in DNM counts and putative impact across affected and unaffected siblings, but did not find significant differences between disease groups, likely owing to the enrichment for recessive disorders in this part of the world, or the small sample size per clinical condition. This study serves as a reference for DNM discovery in multiplex families from the globally under-represented populations of the Middle-East.

Clinical and pathological features and phenotype-genotype correlation of pheochromocytoma and paraganglioma in a highly consanguineous population

Clinical and pathological features and phenotype-genotype correlation of pheochromocytoma and paraganglioma in a highly consanguineous population

Mutation spectrum of congenital heart disease in a consanguineous Turkish population.

BackgroundsWhile many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts.MethodsWe recruited 73 CHD probands from consanguineous families in Turkey and used whole‐exome sequencing (WES) to identify genetic lesions in these patients.ResultsOn average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss‐of‐function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D‐TGA). Three additional patients (4.1%) harbored other types of CHD‐associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity.ConclusionsOur WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.

The genetic elucidation of monogenic obesity in the Arab world: a systematic review.

Investigation of monogenic obesity (MO), a rare condition caused by a single gene variant(s), especially in consanguineous populations, is a powerful approach forobtaining novel insights into the genetic alterations involved. Here, we present a systematic review of the genetics of MO in the 22 Arab countries and apply protein modeling in silico to the missense variants reported. We searched four literature databases (PubMed, Web of Science, Science Direct and Scopus) from the time of their first creation until December 2020, utilizing broad search terms to capture all genetic studies related to MO in the Arab countries. Only articles published in peer-reviewed journals involving subjects from at least one of the 22 Arab countries and dealing with genetic variants related to MO were included. Protein modelling of the variants identified was performed using PyMOL. The 30 cases with severe early-onset obesity identified in 13 studies carried 14 variants in five genes (LEP, LEPR, POMC, MC4R and CPE). All of these variants were pathogenic, homozygous and carried by members of consanguineous families. Despite the elevated presence of consanguinity in the Arab countries, the genetic origins of MO remain largely unexplained and require additional studies, both of a genetic and functional character.

EP069: Possible founder variant and spectrum of phenotypic manifestation of Fukuyama muscular dystrophy reported in four unrelated Pakistani families

Monogenic Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous group of disorders with about 500 associated genes. NMDs may be inherited in autosomal recessive, autosomal dominant and X-linked fashion. In the context of highly consanguineous Pakistani population, we expect the autosomal recessive NMDs to have a higher prevalence, compared to that seen in the populations with European ancestry. However, we do not have contextual ethno-specific genomics data for NMDs in Pakistani population.

Understanding discrepancy in autism epidemiology in view of underpinning genetic architecture: Lessons learnt from studies in consanguineous populations

This short commentary aims to shed light on the discrepancy in the epidemiological findings and underlying genetic architecture of Autism Spectrum Disorder (ASD) between demographically distinct populations; consanguineous and non-consanguineous. Here we discuss the effect of advanced paternal age as a risk factor acting as a proxy for potential underlying genetic mechanisms. On that account, this narrative postulates that disparity might possibly be explained in the context of the differences in genetic makeup and abundance of recessive mutations in the highly consanguineous populations.

Fine-Scale Genetic Structure in the United Arab Emirates Reflects Endogamous and Consanguineous Culture, Population History, and Geography.

The indigenous population of the United Arab Emirates (UAE) has a unique demographic and cultural history. Its tradition of endogamy and consanguinity is expected to produce genetic homogeneity and partitioning of gene pools while population movements and intercontinental trade are likely to have contributed to genetic diversity. Emiratis and neighboring populations of the Middle East have been underrepresented in the population genetics literature with few studies covering the broader genetic history of the Arabian Peninsula. Here, we genotyped 1,198 individuals from the seven Emirates using 1.7 million markers and by employing haplotype-based algorithms and admixture analyses, we reveal the fine-scale genetic structure of the Emirati population. Shared ancestry and gene flow with neighboring populations display their unique geographic position while increased intra- versus inter-Emirati kinship and sharing of uniparental haplogroups, reflect the endogamous and consanguineous cultural traditions of the Emirates and their tribes.

Consanguinity and Congenital Heart Disease Susceptibility: Insights into Rare Genetic Variations in Saudi Arabia.

Congenital heart disease (CHD) encompasses a wide range of structural defects of the heart and, in many cases, the factors that predispose an individual to disease are not well understood, highlighting the remarkable complexity of CHD etiology. Evidence of familial aggregation of CHD has been demonstrated in different communities and for different cardiac lesions. Consanguinity, particularly among first cousins, is an added risk factor for these families, particularly in societies where it is considered a common cultural practice, as confirmed in previous studies conducted in Saudi Arabia and other countries. Through comprehensive genetic testing of affected families, we have been able to better understand the genetic basis of the various cardiac lesions and to delineate the molecular mechanisms involved in cardiac morphogenesis. In this review, we discuss the epidemiology and genetics of CHD in consanguineous populations focusing on Saudi Arabia as an extensive study model to address current advances and challenges in the clinical genetic diagnosis and prevention of CHD.

Inborn Errors of Metabolism Referrals- Shahid Sadoughi Hospital: A Cross- Sectional Study

Background: Inborn Errors of Metabolism (IEMs) are a group of heterogeneous disorders resulting from absent or decreased metabolic pathway activity. They are typically rare, but are more common in consanguineous population. Methods: In this cross sectional study, all children with symptoms suspicious for IEMs who referred to Shahid Sadoughi Hospital in Yazd during a 5-year period (2013-2018) were investigated for metabolic diseases. The diagnoses were further confirmed by clinical symptoms and biochemical analysis. IEMs type, age of diagnosis, family history and disease outcome were recorded. Results: In this study, 39 symptomatic children with a median age of 48 months were diagnosed with different types of metabolic diseases. About 64.1% of the patients were born from consanguineous marriage. The patients’ mean age at the time of diagnosis was 25.3 ± 5.1 months. The most frequent disorders were organic acidemias which were found in 12 patients (30.8%), lysosomal storage disorders which were found in 8 patients (20.5%), and amino acid disorders excluding phenylketonuria which was found in 8 patients (20.5%). Most of the patients (60%) were diagnosed before the age of 6 months. Mortality from metabolic disorders was 5 (12.8%). The rest of the patients (22 cases, 56.4 %) had developmental delay. Conclusion: It was found that the prevalence of inherited metabolic disorders was higher in countries with a high prevalence of consanguineous marriage, such as Iran. More extensive newborn screening is needed for ensuring early diagnosis of these patients given that delay in diagnosis of this disorder may be associated with high morbidity and mortality.

Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan.

Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signaling. In a previous study, next-generation sequencing revealed a monogenic etiology in ∼50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity-causing genes in young adults with severe obesity from the same region. Genomic DNA from 126 randomly selected young adult obese subjects (BMI 37.2 ± 0.3 kg/m2; age 18.4 ± 0.3 years) was screened by conventional or augmented whole-exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin, and cortisol levels were measured by ELISA. We identified 13 subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1, and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe nine homozygous mutations (seven missense, one stop-gain, and one stop-loss) and four copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies. Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts.

Consanguineous marriages and their effects on non-communicable diseases in the Moroccan population: a cross-sectional study

Introductionla consanguinité est reconnue dans de nombreuses études comme un facteur appréciable affectant la santé de l´individu sur plusieurs générations et pose un problème réel de santé publique. Cette étude vise à déterminer les effets de la consanguinité sur les maladies non transmissibles, en particulier la susceptibilité à une série de maladies chroniques et complexes dans la population marocaine.Méthodesc´est une étude transversale analytique basée sur un sondage mené dans deux communes marocaines Bni hlal et Foum jemaa. L'échantillon étudié comportait 222 individus. Les rapports de côtes avec leurs intervalles de confiance à 95% ont été calculés pour la probabilité de maladie selon le statut de consanguinité. Le test du Chi 2 été utilisé pour vérifier l'association entre les variables catégorielles. Une valeur de P < 0,05 était considérée comme significative.Résultatsune fréquence de 43.2% des mariages consanguins a été enregistré chez les répondants contre 41% chez leurs parents. Nous avons remarqué que la consanguinité entre les parents augmente les chances de mariage consanguin parmi leurs progénitures (p = 0.01). La génération issue des parents consanguins a un risque plus élevé de maladies non transmissible telles que les cancers, le diabète, les maladies cardiovasculaires, les maladies respiratoires chroniques et l´insuffisance rénale chronique.Conclusionla présente étude a révélé une augmentation de la prévalence des maladies non transmissibles dans la population consanguine. Cela peut confirmer le rôle des facteurs génétiques dans l'ensemble du spectre de la maladie et pas seulement pour les troubles mendéliens.