High Rate Of Consanguinity Research Articles

Clinical and Molecular Characterization of Mucopolysaccharidosis Type 3A and 3B in a Turkish Series

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease. Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported. Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532−?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect. Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

Genetic and clinical characterization of Niemann-Pick disease type C with homozygous NPC1 gene mutation: insights from whole exome sequencing and advanced neuroimaging of two familial cases

Background: Niemann-Pick disease Type C (NPC) is a rare genetic lipid storage disorder characterized by heterogeneous clinical presentations primarily affecting the neurological and visceral systems. This study aims to elucidate the clinical manifestations, radiological findings, and genetic characteristics of NPC, emphasizing the implications of familial aggregation and consanguinity. Case Presentation: We present two cases from a single family, detailing the clinical progression, radiological findings, and genetic mutations. Case 1 involves a 39-year-old male exhibiting symptoms such as dysarthria, cerebellar ataxia, and progressive neurological decline over eight years. Case 2, a relative aged five, displays similar early-onset neurological symptoms. Both cases demonstrate significant cerebellar atrophy on MRI and share a familial NPC1 gene mutation, suggesting a hereditary pattern influenced by consanguineous relationships. Whole Exome Sequencing identified a pathogenic homozygous mutation in the NPC1 gene, confirming the diagnosis of NPC. This finding underscores the genetic basis of the disease and highlights the role of familial genetics in its pathogenesis. Conclusion: These cases underscore the critical role of genetic testing, particularly whole exome sequencing, in diagnosing NPC, which can often present with diverse clinical symptoms. The familial clustering observed also draws attention to the genetic counseling needs in populations with high rates of consanguinity, emphasizing the importance of community genetic studies to understand and manage such rare disorders.

First Cousin Marriages and the Risk of Childhood-Onset Vitiligo: Exploring the Genetic Background: A Cross-Sectional Study.

Vitiligo, a condition characterized by depigmented skin, has been observed to have a higher incidence in patients with a family history of the disease. This study investigates the relationship between parental consanguinity, family medical history, and the onset of childhood vitiligo, hypothesizing that genetic factors play a significant role. A cross-sectional study was conducted involving 382 people diagnosed with vitiligo in Saudi Arabia. The study assessed the prevalence of parental consanguinity and its correlation with the disease's onset, employing statistical analysis to evaluate the data collected through medical records and family history questionnaires. The findings reveal a significant association between parental consanguinity, particularly among first cousins, and the incidence of childhood-onset vitiligo. Additionally, a notable correlation was found between family medical history and the onset of the condition, with familial vitiligo being more prevalent in patients with adult-onset vitiligo. This study underscores the critical role of genetic predispositions in the development of childhood-onset vitiligo, highlighting the influence of parental consanguinity. The results advocate for increased awareness and screening in populations with high rates of consanguinity to facilitate early detection and management of vitiligo. Future research should focus on exploring the genetic mechanisms underlying this association to develop targeted interventions.

A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.

Uncovering myocardial infarction genetic signatures using GWAS exploration in Saudi and European cohorts

Genome-wide association studies (GWAS) have yielded significant insights into the genetic architecture of myocardial infarction (MI), although studies in non-European populations are still lacking. Saudi Arabian cohorts offer an opportunity to discover novel genetic variants impacting disease risk due to a high rate of consanguinity. Genome-wide genotyping (GWG), imputation and GWAS followed by meta-analysis were performed based on two independent Saudi Arabian studies comprising 3950 MI patients and 2324 non-MI controls. Meta-analyses were then performed with these two Saudi MI studies and the CardioGRAMplusC4D and UK BioBank GWAS as controls. Meta-analyses of the two Saudi MI studies resulted in 17 SNPs with genome-wide significance. Meta-analyses of all 4 studies revealed 66 loci with genome-wide significance levels of p < 5 × 10–8. All of these variants, except rs2764203, have previously been reported as MI-associated loci or to have high linkage disequilibrium with known loci. One SNP association in Shisa family member 5 (SHISA5) (rs11707229) was evident at a much higher frequency in the Saudi MI populations (> 12% MAF). In conclusion, our results replicated many MI associations, whereas in Saudi-only GWAS (meta-analyses), several new loci were implicated that require future validation and functional analyses.

Incidence and prevalence of neurological disorders in the United Arab Emirates: a systematic review

Background/ObjectivesThe United Arab Emirates (UAE) is a rapidly developing country. With the increase in average life-expectancy, high rates of consanguinity, and the adoption of a Western lifestyle, the burden of neurological disorders is expected to increase over the next few decades. Despite the importance of neurological disorders, there has not been a systematic review of published studies on the epidemiology of neurological disorders in the UAE.MethodsWe searched for studies of incidence and/or prevalence of neurological disorders in the UAE published in English in MEDLINE, Google Scholar, Embase, and Scopus databases with no date restrictions up until 01 October 2023. Two authors independently assessed abstracts and full texts of possibly relevant papers, followed by data extraction from studies satisfying the eligibility criteria.ResultsEight articles (N = 2067 patients) were included, half reported incidence and prevalence of multiple sclerosis, with an average crude prevalence 56/100,000 and related demyelinating disorders. Others were related to headache, meningitis, cerebral venous thrombosis, and brain tumours.ConclusionThere is a distinct lack of data on the epidemiology of different neurological diseases in the UAE. Large population-based studies, ideally longitudinal, are required to provide accurate and reliable estimates of the incidence and prevalence of neurological disorders to help inform healthcare capacity planning.

Phenotype and disease course differences in monogenic and sporadic childhood lupus.

To report the differences in phenotypic characteristics, disease course, and outcome in monogenic and sporadic childhood lupus (SC-lupus) from a single tertiary childhood lupus clinic. A descriptive, observational, cross-sectional study was conducted. Data were retrospectively collected at the last follow-up visit on patients with monogenic lupus proven by genetic variants and SC-lupus seen between June 1997 and July 2022. SC-lupus patients were selected by systematic sampling from lupus patients presenting to our lupus clinic; the first patient was chosen randomly, and the subsequent patients were chosen at intervals of three. Data comprised the clinical and laboratory findings, disease activity using the SLEDAI, and damage measured by the pSDI. A total of 54 patients with a median disease duration of 6.8 (IQR 3.5-10.5) years were included. There were 27 patients with monogenic lupus and 27 patients with SC-lupus, with a median age at disease onset of 3.5 (IQR 1.0-6.0), and 9.5 (IQR 7.0-11.8), respectively. (p < 0.05). The rate of consanguinity and family history of lupus were higher in monogenic lupus patients. The two groups were comparable. However, monogenic lupus patients showed more gastrointestinal tract symptoms, and failure to thrive (p < 0.05). They also had more infections. The frequency of the autoantibody profile was higher in monogenic lupus patients. Belimumab was more frequently used in monogenic lupus while rituximab in SC-lupus patients. Monogenic lupus patients had a higher mean SLEDAI, but statistically, it was insignificant. Patients with monogenic lupus had greater disease damage, with a higher mean pSDI and a higher mortality rate (p < 0.05). Patients with monogenic lupus are likely to have an early disease onset and a strong family history of lupus, as well as a guarded prognosis, which is likely due to the disease's severity and frequent infections. These differences may be related to the high consanguinity rate and underlying genetic variants.

Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience

Objectives To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). Methods This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. Results A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. Conclusions The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.

THU232 Genetic Study In A Series Of 29 Triple A Syndrome Patients From 19 Sudanese Families - Identification Of Two Novel AAAS Mutations

Abstract Disclosure: K. Koehler: None. F. Quitter: None. D. Landgraf: None. E. Streiff: None. M.A. Abdullah: None. S.S. Hassan: None. A. Huebner: None. S.A. Musa: None. Triple A syndrome (MIM*231550) is a rare autosomal recessive multisystemic disorder characterized by adrenal insufficiency, achalasia, alacrima and neurologic impairments. It is caused by defects in the nucleoporin ALADIN due to mutations in the encoding AAAS gene. We report the genetic and clinical data of triple A syndrome in a series of Sudanese children treated at the Gaafar Ibn Auf Children’s Tertiary Hospital, the largest children's referral hospital in Sudan. The initial diagnosis of triple A syndrome was based on pathognomonic clinical signs and symptoms. Furthermore, early morning serum cortisol levels below the reference range (&amp;lt;6 μg/dl) with high ACTH levels (&amp;gt;100 pg/ml) and/or cortisol below 500 nmol/l in an ACTH stimulation test as well as pathological barium swallow and Schirmer-test were criteria for diagnosis. The medical diagnosis was finally confirmed by mutation detection in the AAAS gene.We genetically investigated 19 families including 29 patients with clinically diagnosed triple A syndrome. We identified six different AAAS mutations mainly in a homozygous form including three nonsense mutations, one frameshift mutation leading to a truncated protein and two splice defects, among them the North African founder mutation c.1331+1G&amp;gt;A (intron 14) in 32 % (6 families). An 8 bp-deletion at the junction of exon 4/intron 4 in two families is a novel, yet undescribed mutation (c.394_399+2delCTGTCTGT). As this mutation destroys a donor splice site, it results in alternative splicing skipping exon 4, altering the protein sequence after amino acid E102 and leading to a premature stop codon shortly after. This is most likely associated with functional impairment of the truncated ALADIN protein. The second novel AAAS mutation is a 1 bp-deletion in exon 9 in three families, which results in a frameshift at amino acid tryptophan 284 and consequently a premature stop codon at position 7 of the new reading frame (c.852_852delG, p.Trp284Cysfs*7, or shortly p.W284fs). The most frequent mutation in this large Sudanese patient series was a previously described mutation in exon 9 (c.934C&amp;gt;T, p.Arg312*) present in 37 % (seven families).Genotype/phenotype analyses revealed a highly variable occurrence of the three main symptoms, age of onset and severity of the disease between patients with the same AAAS mutation and even within one family. The rate of 95 % mutations in a homozygous form reflects the high rate of consanguinity in the Sudanese population.In summary, triple A syndrome seems to be an underdiagnosed disease outside a specialized paediatric endocrinological department in Sudan as many cases presented late with adrenal crises. An early molecular genetic diagnosis, e.g. in siblings, can be important to avoid hypoglycaemic crises with a potential lethal outcome. Presentation: Thursday, June 15, 2023

Influence of autozygosity on common disease risk across the phenotypic spectrum

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes& Health (n= 23,978 British South Asians), UK Biobank (n= 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n= 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

XERODERMAPIGMENTOSUM: EPIDEMIOLOGICAL, CLINICAL AND THERAPEUTIC ASPECTS

Xeroderma Pigmentosum (XP) is a rare and disabling genetic dermatosis that was first described in 1874. It is characterized by photo-induced cutaneous alterations, often associated with ocular lesions and sometimes with neurological involvement. The transmission of XP is on an autosomal recessive mode, and it is relatively frequent in countries with high consanguinity rates and large family sizes, such as those in the Maghreb region. This study aims to present an epidemiological, clinical, and histological profile of XP patients treated in the plastic surgery department in southern Morocco, reflecting the regions epidemiological reality and specifying the modalities of oncologic and reparative surgical treatment.

Clinical, Immunological, and Genetic Findings in Iranian Patients with MHC-II Deficiency: Confirmation of c.162delG RFXANK Founder Mutation in the Iranian Population.

Major histocompatibility complex class II (MHC-II) deficiency is a rare inborn error of immunity (IEI). Impaired antigen presentation to CD4 + T cells results in combined immunodeficiency (CID). Patients typically present with severe respiratory and gastrointestinal tract infections at early ages. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy. We describe the clinical, immunologic, and genetic features of eighteen unrelated Iranian patients with MHC-II deficiency. Consanguinity was present in all affected families. The median age at the initial presentation was 5.5months (range 7days to 18years). The main symptoms included failure to thrive, persistent diarrhea, and pneumonia. Autoimmune and neurologic features were also documented in about one-third of the patients, respectively. Thirteen patients carried RFXANK gene mutations, two carried RFX5 gene mutations, and three carried a RFXAP gene mutation. Six patients shared the same RFXANK founder mutation (c.162delG); limited to the Iranian population and dated to approximately 1296years ago. Four of the patients underwent HSCT; three of them are alive. On the other hand, nine of the fourteen patients who did not undergo HSCT had a poor prognosis and died. MHC-II deficiency is not rare in Iran, with a high rate of consanguinity. It should be considered in the differential diagnosis of CID at any age. With the limited access to HSCT and its variable results in MHC-II deficiency, implementing genetic counseling and family planning for the affected families are mandatory. We are better determined to study the c.162delG RFXANK heterozygous mutation frequency in the Iranian population.

E37 Clinical and demographic criteria of Juvenile primary systemic vasculitis in Libyan Children

Abstract Introduction Primary vasculitis syndromes are rare in childhood. The clinical manifestations depend on the vessels involved and can lead to significant mortality and morbidity. Aim To study demographic and clinical characteristics of patients with diagnosed with vasculitis other than Kawazaki disease and Henoch-Schonlein purpora (HSP) and to report the outcome of the patients. Materials and methods This is a case series conducted by reviewing the files of patients diagnosed with vasculitis and followed up at the pediatric rheumatology unit of the Tripoli Children Hospital, Libya from year 2000–2022. Data regarding patients’ demography, time of diagnosis, clinical features, laboratory results, treatment and complications were retrieved. Results A total of 37 cases included in the study. 17 (45.9%) were males and 20 (54%) were females followed up for a mean period of 4.48 ± 4.21. Mean age at diagnosis was 8.39 ± 3.84 years. Regarding the diagnosis, there were 3 (8.1%) patients with Takayasu arteritis, 5 (13.5%) patients with polyarteritis nodosa, 2 (5.4%) patients with cutaneous polyarthritis nodosa, 1 (2.7%) patients with granulomatosis with polyahgitis, 1 (2.7%) patient with microscopic polyangiitis, 3 (8.1%) patients with Chrug-Strauss disease, 16 (43.2%) patients with Behcet disease, 1 (2.7%) patients with cogan syndrome, 3(8.1%) patients with urticarial vasculitis, 1 (2.7%) patient with hypocomplementaemic vasculitis, and 1 (2.7%) patient with DADA2. Mean period between the start of symptoms and diagnosis was 1.4 ± 2.8 years. In 6 (16.2%) of the patients there was family history of vasculitis and in 11 (29.7%) the parents are consanguineous. Angiography revealed abnormalities in 5 (13.5%) of the patients. Skin biopsy was done in 4 (10.8%) patients [2 patients with polyarthritis nodosa and 2 patients with urticarial vasculitis] and renal biopsy was done in 1 (2.7%) patient. Steroid was used in 24 (64.9%), Azathioprine in 4 (10.8%) patients. Cellcept was used in 10 (27%) of the patients. Ciclosporin was used 1(2.7%) patient, cyclophosphamide in 3 (8.1%) patients and Immunoglobulin in 6 (16.2%) of patients. Biologics were used in six patients, adalimumab in one patient which was discontinued because of recurrent abscess. In the two patients who used infliximab, treatment was effective. Three patients were treated with tocilizumab, it was ineffective in two, therefore discontinued. However, tocilizumab was effective in one patient with Takayasu arteritis. Complications developed in 23 (62.2%). Muscle atrophy in 1, deforming arthritis in 1, osteoporosis in 1, mouth ulcers in 2, hypertension in 2, hearing loss in 1, chronic sinusitis in 1, cardiovascular accident in 1, cataract in 1, visual impairment in 3, proteinuria in 2, pulmonary fibrosis in 1, chronic asthma in 3, impaired renal function in 1. Conclusion This is the first report of pediatric vasculitis cases in Libya. It showed a heterogeneous spectrum of vasculitis with high rate of consanguinity and low rate of reported family history of vasculitis. Hopefully this report will increase awareness among clinicians of vasculitis and more cases will be diagnosed.

Genotype-Phenotype Analysis of Children with Epilepsy Referred for Whole-Exome Sequencing at a Tertiary Care University Hospital.

Despite the high consanguinity rates, data on genetic epilepsy in Saudi Arabia is limited. The objective of the current study was to characterize genetic mutations associated with epilepsy in pediatric patients and describe their phenotypic presentations. A retrospective chart review was conducted among children presented with epilepsy in one center in Saudi Arabia between 2015 and 2018. Only those who had undergone genetic testing were included. A total of 45 patients had positive whole-exome sequencing (WES) genetic testing with 37 mutations. Six mutations (SCN1A, DENND5A, KCNQ2, ACY1, SCN2A, and PCDH19) were repeated in 15 patients, with largely heterogeneous phenotypic presentations in patients with the same mutation. Several mutations are reported for the first time in Saudi Arabia. The median age at epilepsy onset was four months. Consanguineous parents and family history of epilepsy were frequent (31.8% and 33.3%, respectively). Developmental delay (44.4%), cognitive delay (42.2%), language delay (40.0%), behavioral features (28.9%), and microcephaly (20.0%) were frequent presentations. At initial diagnosis, 68.9% of EEG and 48.9% of brain MRI were abnormal. The most currently used antiseizure medications (ASMs) were levetiracetam (48.9%), topiramate (28.9%), and valproic acid (20.0%). Approximately 60% of the patients were controlled with (47.6%) or without (11.9%) ASMs, and three (7.1%) patients died. Multiple mutations among children with epilepsy are reported in one hospital in Saudi Arabia, with the majority reported for the first time. The current findings highlight the importance of doing genetic testing for the evaluation of childhood epilepsy.

Mitochondrial depletion syndrome type 3: the Lebanese variant.

Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.

The use of multiplex ARMS-PCR for mutational analysis of beta-globin gene in consanguineous population of KP Pakistan

Purposeß-thalassemia is a hereditary disorder due to mutation in the ß-globin gene on chromosome 11. Out of 200 known ß-globin gene chain mutations recognized, it is better to identify the most common mutation in specific regions and ethnicity for cost-effective molecular diagnosis of this disorder. Therefore, this study aims to practice multiplex-amplification refractory mutation system (ARMS) PCR on patients with thalassemia in Khyber Pakhtunkhwa (KP) to investigate the most common mutations in the ß-globin chain gene.Design/methodology/approachTwenty-two individuals (patients, their parents and non-affected siblings) with signed consent were studied from six consanguineous families of ß-thalassemia. Blood samples were collected for DNA isolation. For the detection of mutations in the ß-globin gene, ARMS-PCR was used. The amplicon was visualized through 2% Agarose Gel.FindingsThe most common mutations among different ethnic groups in the study area residents were Fr 8-9 (+G) and IVS 1-5 (G&gt; C). The prominent enhancing factors for ß-thalassemia are inter-family marriages and lack of awareness.Practical implicationsMultiplex ARMS_PCR is the most valuable technique for assessing multiple mutations in a single reaction tube.Social implicationsDue to extensively found ethnic and regional variations and a high rate of consanguinity, the Pashtun population has a great risk of mutations in their genome. Therefore, ARMS-PCR is a cost-effective mutational diagnostic strategy that can help to control disease burden.Originality/valueLimited studies using ARMS-PCR for mutational analysis in the ß-globin gene are conducted. This study is unique as it targeted consanguineous families of KP Pakistan.

South Asian medical cohorts reveal strong founder effects and high rates of homozygosity

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.

Identification of founder and novel mutations that cause congenital insensitivity to pain (CIP) in palestinian patients

BackgroundCongenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient’s life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations in NTRK1 and NGF genes, and is characterized by mental retardation and the inability to sweat (Anhidrosis). Because of high consanguinity rates in Palestine, this rare disease appears to have a higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community.MethodsIn our study, we used Sanger and Whole exome sequencing to genotype members of five CIP-affected Palestinian families.ResultsOur results confirm the presence of the founder c.1860-1861insT mutation in the NTRK1 gene of Palestinian Bedouin CIPA patients. Furthermore, one CIPA family carried a missense c.2170 G > A (G724 S) mutation in exon 16 of the NTRK1 gene. Finally, a novel nonsense c.901 A > T mutation (K301*) was detected in exon 7 of the SCN9A gene in CIP without anhidrosis family.ConclusionsOur study revealed three mutations that cause CIP and CIPA in the Palestinian community, which can help in improving the process of diagnosis and genetic counseling and establishing protocols for the diagnosis and follow-up for the affected individuals. This is especially important given that early diagnosis and medical care interference can prevent unpleasant CIP and CIPA complications.

Spectrum of genetic disorders and gene variants in the United Arab Emirates national population: insights from the CTGA database.

Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.