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 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.

BACKGROUND: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. OBJECTIVE: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. METHODS: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. RESULTS: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4% of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3% of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17% of patients). These disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5% of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. CONCLUSIONS: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

Clinical and Molecular Update on the Fourth Reported Family with Hamamy Syndrome.

We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe telecanthus, abnormal ears, dentinogenesis imperfecta, and bone fragility. Whole-exome sequencing studies performed on the 2 affected individuals and one obligate carrier revealed the presence of a homozygous c.503G>A (p.Arg168His) missense mutation in IRX5 in both sibs, not reported in any other family. Review of the literature and differential diagnoses are discussed.

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.

Developmental delay, intellectual disability, short stature, subglottic stenosis, hearing impairment, onychodysplasia of the index fingers, and distinctive facial features: A newly reported autosomal recessive syndrome.

We report on a multiply consanguineous Syrian family where two siblings, a boy and a girl, presented with a compilation of symptoms including developmental delay, severe intellectual disability, absent speech, hearing impairment, short stature, subglottic stenosis, increased length of the palpebral fissures, onychodysplasia of index fingers, scoliosis, genu valgum, and malpositioned toes. Two other individuals from the extended family with similar clinical features are also described. Array-CGH did not reveal any pathological copy number variation. Exome sequencing failed to find any causal variants. Differential diagnoses and the possibility that we might be reporting a hitherto unknown syndrome are discussed.

Homozygous deletion of exons 2-7 within TGFB3 gene in a child with severe Loeys-Dietz syndrome and Marfan-like features.

We describe a patient with palatal abnormalities-cleft palate and bifid uvula; distinctive facial features-long and triangular face, large ears and nose, thin lips and dental crowding; musculoskeletal abnormalities-severe scoliosis, joint laxity, long digits, flat feet, decreased muscle mass, and diminished muscle strength; and cardiac features-a dilatated ascending aorta at the level of Valsalva sinuses and a patent foramen ovale. Sequence analysis and deletion/duplication testing for a panel of genes involved in connective tissue disorders revealed the presence of a novel homozygous deletion of exons 2-7 in TGFB3 gene. Heterozygous pathogenic mutations in TGFB3 have been associated with Loeys-Dietz syndrome 5 (LDS5) and Arrhythmogenic Right Ventricular Dysplasia type 1. Here, we report the first case of a homozygous TGFB3 variant associated with a severe LDS5 and Marfan-like presentation.

Expanded PCH1D phenotype linked to EXOSC9 mutation.

Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM_001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder.

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.

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.

A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).

Joubert syndrome (JS) is an autosomal or X-linked recessive syndrome principally characterized by hypotonia, ataxia, cognitive impairment, and a specific finding on brain imaging called a "molar tooth sign" (MTS), which can be isolated or in conjunction with variable organ involvement. The genetic basis of JS is heterogeneous, with over 35 ciliary genes being implicated in its pathogenesis. However, some of these genes (such as PDE6D) have been associated to JS only in single families, seeking confirmation. Here we report a boy, born to first cousin parents, presenting with developmental delay, hypotonia, microcephaly, post axial polydactyly, oculomotor apraxia, and MTS. Whole exome sequencing revealed the presence of a novel homozygous truncating variant in the PDE6D gene: NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]. The variant was confirmed by Sanger sequencing and found at the heterozygous state in both parents. A review of the literature pertaining to the role of PDE6D in JS 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.

A novel, putatively null, FGD1 variant leading to Aarskog-Scott syndrome in a family from UAE.

BACKGROUND: The X-linked condition "Aarskog-Scott syndrome (AAS)" causes a characteristic combination of short stature, facial, genital and skeletal anomalies. Studies elucidated a causative link between AAS and mutations in the FGD1 gene, which encodes a Rho/Rac guanine exchange factor. FGD1 is involved in regulating signaling pathways that control cytoskeleton organization and embryogenesis. CASE PRESENTATION: FGD1 was studied in an Emirati family with two cases of AAS using PCR amplification and direct sequencing of the entire coding region of the gene. Various in silico tools were also used to predict the functional consequences of FGD1 mutations. In the reported family, two brothers harbor a novel hemizygous mutation in FGD1 c.53del (p.Pro18Argfs*106) for which the mother is heterozygous. This frameshift deletion, being close to N-terminus of FGD1, is predicted to shift the reading frame in a way that it translates to 105 erroneous amino acids followed by a premature stop codon at position 106. Full molecular and clinical accounts about the variant are given so as to expand molecular and phenotypical knowledge about this disorder. CONCLUSIONS: A novel variant in FGD1 was found in an Emirati family with two brothers suffering from AAS. The variant is predicted to be a null mutation, and this is the first report of its kind from the United Arab Emirates.