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.

A case report on probable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing following vairechanika nasya in Ménière's disease.

A 62 year old woman diagnosed with Ménière's disease, who underwent vairechanika nasya (VN) with shadbindu taila presented with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) like phenomena immediately after the procedure. Rescue measures of abhyanga (local oil massage) and nadi sweda (local fomentation) were administered. Within half an hour the symptoms considerably declined and after 1 hour got completely relieved. The exact symptom disclosure by the patient who herself was a doctor helped in detecting the classic pattern of 'saw tooth phenomena' giving leads into a rare manifestation of probable SUNCT. Naranjo scale yielded zero score and thus the probable causality of VN with shadbindu taila could not be established so as to cause probable SUNCT as an adverse drug reaction (ADR). This case study is not put up for reporting an ADR of VN with shadbindu taila; rather this illustrates an uncommon, yet imperative adverse event of probable SUNCT while undergoing nasya procedure probably due to judgment error while fixing the VN dose in a patient with Ménière's disease. Transparent reporting of such unusual events during panchakarma procedures is necessary so that clinicians can understand, evaluate and take appropriate initiatives to manage them.

An Ayurvedic personalized prophylactic protocol in COVID-19.

The current COVID-19 pandemic brought about by the SARS-CoV-2, a novel ß coronavirus is creating intense health havoc globally. Researchers suspect the situation to stay for long in the community, considering this virus's pathogenesis, high rate transmission and tendency to provoke uncontrolled immune response activation. Immune mechanisms are highly individualistic. We put forward a hypothetical model of prakruti (Ayurvedic body phenotyping character) based personalized prophylactic-therapeutic strategies aiming at a better immunomodulation and quicker resolution of host immune mechanisms. We propose this model in symptomatic, mild to moderate, COVID-19 diagnosed cases and in cases quarantined for high to low risk primary contact with a positive case. We also suggest a community level personalized Ayurvedic prophylactic-therapeutic strategy based on the DOTS model. Person-centered body purificatory measures (panchakarma procedures) like therapeutic purgation (virechana) and medicated enema (basti) are suggested in this hypothetical protocol with justification on evidence-based links between immune responses and prakruti along with specific jwara (fevers of varied origin as per Ayurvedic sciences) and COVID-19 symptomatology. The paper also appraises the importance of pitta dosha/ama dosha in the manifestation of inflammation driven destructive phase of immune responses along with its stage-wise intervention. This hypothetical model intends to open up discussions on significance of prakruti assessment as a predictive marker to screen people who are at risk of succumbing into deteriorating states if infected with COVID-19. It also intends to discuss the predictive personalized medicine measures based on prakruti in yielding individual host immune homeostasis which may positively reduce the chances of untoward events of an aggravated immune responsiveness and subsequent inflammation driven tissue destruction - the candidate causes for COVID-19 related casualties. Testing this model may give insight towards emphasizing personalized host immune coping mechanisms that may prove crucial in any infectious outbreaks in near future too.

Catalogue for Transmission Genetics in Arabs (CTGA) Database: Analysing Lebanese Data on Genetic Disorders.

Lebanon has a high annual incidence of birth defects at 63 per 1000 live births, most of which are due to genetic factors. The Catalogue for Transmission Genetics in Arabs (CTGA) database, currently holds data on 642 genetic diseases and 676 related genes, described in Lebanese subjects. A subset of disorders (14/642) has exclusively been described in the Lebanese population, while 24 have only been reported in CTGA and not on OMIM. An analysis of all disorders highlights a preponderance of congenital malformations, deformations and chromosomal abnormalities and demonstrates that 65% of reported disorders follow an autosomal recessive inheritance pattern. In addition, our analysis reveals that at least 58 known genetic disorders were first mapped in Lebanese families. CTGA also hosts 1316 variant records described in Lebanese subjects, 150 of which were not reported on ClinVar or dbSNP. Most variants involved substitutions, followed by deletions, duplications, as well as in-del and insertion variants. This review of genetic data from the CTGA database highlights the need for screening programs, and is, to the best of our knowledge, the most comprehensive report on the status of genetic disorders in Lebanon to date.

Clinical and Genetic Features of Patients With Fanconi Anemia in Lebanon and Report on Novel Mutations in the FANCA and FANCG Genes.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and presents with cytopenias, characteristic physical features, increased chromosomal breaks, and a higher risk of malignancy. Genetic features of this disease vary among different ethnic groups. We aimed to identify the incidence, outcome, overall condition, and genetic features of patients affected with FA in Lebanon to optimize management, identify the most common genes, describe new mutations, and offer prenatal diagnosis and counseling to the affected families. Over a period of 17 years, 40 patients with FA were identified in 2 major diagnostic laboratories in Lebanon. Information was obtained on their clinical course and outcome from their primary physician. DNA was available in 20 patients and was studied for underlying mutations. FANCA seemed to be the most frequent genetic alteration and 2 novel mutations, one each in FANCA and FANCG, were identified. Nine patients developed various malignancies and died. This is the first study looking at clinical and genetic features of FA in Lebanon, and points to the need for establishing a national and regional registry for this condition.

Evaluating the Impact of Outpatient Multi-Dose Medication Packaging Service (MDMPS) on Medication Adherence and Clinical Outcomes.

BACKGROUND: There is limited understanding on the impact of the multidose medication packaging service (MDMPS). OBJECTIVES: The main objective of this study was to evaluate changes in medication adherence in patients using MDMPS compared to patients receiving standard medication packaging (control group). The other objectives were to determine the association between medication adherence and clinical outcomes, and to assess patients'/caregivers' perceptions toward MDMPS. METHODS: A retrospective cohort study was conducted among primary care patients in Singapore enrolled into MDMPS between 2012 and 2017. Eligible patients were taking at least five chronic medications, diagnosed with Hypertension, Hyperlipidemia and/or Type 2 Diabetes, with prescription records for at least six months before and after the index period. They were matched to control patients based on the type of comorbidities and medication adherence status. Medication Possession Ratio (MPR), glycated hemoglobin (HbA1c), blood pressure and low-density lipoprotein-cholesterol (LDL-C) of both groups were compared between baseline and at least six months post-index period. Interviewer-administered questionnaires were also conducted for MDMPS patients. RESULTS: The MPR of MDMPS patients (n = 100) increased by 0.37% (P < .001) compared to the control group (n = 100). MDMPS patients with diabetes had reduced HbA1c by 0.1% after six months (P = .022) but was not significant after 12 months. No significant changes were seen in blood pressure and LDL-C between both groups. At least 50% of patients were highly satisfied with MDMPS. CONCLUSION: MDMPS can improve medication adherence. Further studies are needed to understand its clinical impact.

Recessive marfanoid syndrome with herniation associated with a homozygous mutation in Fibulin-3.

We have previously reported on a consanguineous family where 2 siblings, a girl and a boy, presented with tall stature, long and triangular faces, prominent forehead, telecanthus, ptosis, everted lower eyelids, downslanting palpebral fissures, large ears, high arched palate, long arm span, arachnodactyly, advanced bone age, joint laxity, pectus excavatum, inguinal hernia, and myopia, suggestive of a new subtype of connective tissue disorder (Megarbane et al. AJMG, 2012; 158(A)5: 1185-1189). On clinical follow-up, both patients had multiple inguinal, crural, and abdominal herniae, intestinal occlusions, several huge diverticula throughout the gut and the bladder, and rectal prolapse. In addition, the girl had a mild hearing impairment, and the boy a left diaphragmatic hernia. Here we describe the molecular characterization of this disorder using Whole Exome Sequencing, revealing, in both siblings, a novel homozygous missense variant in the EFEMP1 gene, c.163T > C; p.(Cys55Arg) whose homozygous by descent, autosomal recessive transmission was confirmed through segregation analysis by Sanger sequencing. In addition, the girl exhibited a homozygous mutation in the MYO3A gene, c.1370_1371delGA; p.(Arg457Asnfs*25), associated with non-syndromic deafness. The siblings were also found to harbor a homozygous nonsense variant in the VCPKMT gene. We review the literature and discuss our updated clinical and molecular findings that suggest EFEMP1 to be the probable candidate gene implicated in this novel connective tissue disease.

Further Delineation of the TRAPPC6B Disorder: Report on a New Family and Review.

Pathogenic variants in the TRAPPC6B gene were recently found to be associated in three consanguineous families, with microcephaly, epilepsy, and brain malformations. Here, we report on a 3.5-year-old boy, born to consanguineous Lebanese parents, who presented with developmental delay, lactic acidosis, postnatal microcephaly, and abnormal brain magnetic resonance imaging. By whole exome sequencing, a novel homozygous likely pathogenic variant in exon 1 of the TRAPPC6B gene (c.23T > A; [p.Leu8*]) was identified. A review of the clinical description and literature is discussed, pointing out the phenotypic heterogeneity associated with mutations in this gene.

Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.

Basel-Vanagaite-Smirin-Yosef syndrome (OMIM 616449) is a rare autosomal recessive genetic disorder characterized by severe developmental delay and variable craniofacial, neurological, cardiac, and ocular anomalies in the presence of variants in the MED25 gene. So far, only a handful of patients have been reported with this condition globally. Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies. By whole-exome sequencing (WES), a homozygous variant was found in the MED25 gene, c.518T>C, predicted to result in a p.Ile173Thr change in the MED25 protein. This change has recently been reported in another Lebanese family. Review of the literature, the importance of this mutation in the Lebanese population, and the possibility that this condition may be underdiagnosed and only effectively detected using molecular techniques such as WES are discussed.

Can the vagus nerve serve as biomarker for vata dosha activity?

This 'discussion paper' raises 'provocative questions' to identify physiological systems underlying vata dosha and candidate biomarkers for vata activity. We explained the strong correlations between survival and homeostatic functions of the parasympathetic vagus nerve, and functions governed by the five major sub-types of vata dosha (Praana, Udana, Vyaana, Samaana, and Apana). Four reasons were provided to hypothesize that vagal activity is a reliable candidate biomarker of important vata dosha functions. First, normal vata dosha and the vagus maintain neural, respiratory, and digestive homeostasis, and dysfunctions in both entities cause very similar diseases. Second, vata dosha regulates higher neural functions such as mental health and behaviour, and the 'polyvagal theory' proposes similar functions for the vagus. Third, the similar roles of vata dosha and vagus in maintaining gut homeostasis, suggest that vagal activity in the 'gut-brain' link is a candidate biomarker of pakwashaya (lower gut), a primary regulatory site for vata dosha. Fourth, the vagus is the only vital nerve whose activity can be reliably measured and manipulated. Indeed, vagal nerve stimulation is a USA-FDA approved therapy for certain ailments attributed to impaired vata dosha. No other nerve or dosha, has such multi-functional and life-sustaining properties. These arguments position vagal activity as a suitable candidate biomarker for certain functions of vata dosha.

COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants?

We report on a girl, born to first-cousin Lebanese parents, with severe intellectual disability, congenital hip luxation, cardiac malformation, short stature, facial dysmorphic features including microcephaly, sparse hair, bilateral epicanthal folds, ataxia, seizures, and elevated lactate and pyruvate levels in serum. Whole exome sequencing was carried out on the patient's DNA. Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found. The potential pathogenicity of these variants, and the possibility that the 2 variants could synergistically act to produce the phenotype reported, is discussed.

Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases.

BACKGROUND: According to the Catalogue of Transmission Genetics in Arabs, less than half of diseases reported in Lebanese patients are mapped. In the recent years, Next Generation Sequencing (NGS) techniques have significantly improved clinical diagnosis, compared to traditional sequencing methods. METHODS: A total of 213 analyses by NGS (167 by whole exome sequencing (WES) and 46 by multigene panels tests) were performed on pediatric patients across different regions of Lebanon over a period of two years (December 2015-December 2017). RESULTS: Neurological disorders were the most frequent referral demand for both WES and gene panels (122/213). Pathogenic, likely pathogenic, or variants of unknown significance were identified in 69.5% of the WES and panel patients combined. Over half of the patients with such variants had an autosomal recessive disorder. A definite molecular diagnosis (pathogenic or likely pathogenic variants) was achieved in 34.1% and 47.8% of the patients studied by WES and the multigene panels, respectively. Thirty-three novel variants were found in the cases that were molecularly solved; 26 of these being identified by WES and seven by the multigene panels. In three consanguineous families, autosomal recessive inheritance of genes previously reported as showing dominant inheritance patterns were found. Biallelism was found in six cases, digenism in four cases, and one case was trigenic. CONCLUSION: Our study thus suggests that NGS tools are valuable for an improved clinical diagnosis, and highlights that the increased adoption of such techniques will significantly further improve our understanding of the genetic basis of inherited diseases in Lebanon.

Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2).

The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report on a novel homozygous mutation in UNC80 in a Palestinian-Emirati patient suffering infantile hypotonia with psychomotor retardation and characteristic facies. This mutation was detected by whole exome sequencing and confirmed using Sanger sequencing in the patient-parents trio. Numerous elements in the patient's phenotype were in agreement with the few reported cases of UNC80 mutations; however there are some notable differences. We present comprehensive clinical and molecular accounts of this mutation in addition to a full review of previously reported patients of UNC80 mutations.

Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs.

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next-generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen-2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single-center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world.

Novel PDE6A mutation in an Emirati patient with retinitis pigmentosa.

Mutations in the PDE6A gene are known to cause a form of retinitis pigmentosa (RP43), characterized by progressive retinal degeneration. We describe an Emirati patient with RP caused by a novel mutation in PDE6A. Clinical diagnosis of RP was made based on clinical evaluation and electroretinograms. The molecular analysis involved performing whole-exome sequencing, which enabled the identification of a homozygous 2-bp deletion (c.1358_1359delAT) in PDE6A, which was predicted to result in a frameshift and premature termination (p.Ile452Serfs*7). The mutation completely removed the catalytic PDEase domain in the protein. The parents were found to be heterozygous carriers of the variant. We thus report the first known case of a pathological variant in the PDE6A gene from the Arabian Peninsula.

Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report.

BACKGROUND: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor. CASE PRESENTATION: This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay. CONCLUSIONS: Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings.

Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

BACKGROUND: Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. METHODS: In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates. In silico tools such as CADD and SIFT Indel were used to predict the functional consequences of these mutations. RESULTS: The here-presented mutations occurred in three genes (ALOX12B, TGM1, ABCA12), and these are a mixture of missense and indel variants with damaging functional consequences on their encoded proteins. CONCLUSIONS: This study presents an overview of the mutations that were found in ARCI-related genes in Arabs and discusses molecular and clinical details pertaining to the above-mentioned Emirati cases and their novel mutations with special emphasis on the resulting protein changes.

A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child.

OBJECTIVE: The aim of this work was to report a case of an Emirati child who presented with developmental delay and multiple congenital abnormalities that are consistent with distal arthrogryposis type 5D. CLINICAL PRESENTATION AND INTERVENTION: The clinical presentation comprised contractures of the shoulders, elbows, and knees in addition to camptodactyly and neck pterygium. The facial dysmorphic features noted include ptosis and microretrognathia. Importantly, left orchidopexy was also observed and corrected surgically. Whole exome sequencing revealed that the patient is homozygous for the novel c.1184+1G>T variant in endothelin-converting enzyme-like 1 (ECEL1). CONCLUSION: This is a case of a novel homozygous splice site mutation in the ECEL1 gene in a child with a phenotype consistent with distal arthrogryposis type 5D. The child was born to consanguineous Emirati parents heterozygous for the novel ECEL1 mutation.