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.

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.

A Report on a Family with TMTC3-Related Syndrome and Review.

Recessive mutations in the TMTC3 gene have been reported in thirteen patients to date exhibiting development delay, intellectual disability (ID), seizures, and muscular hypotonia, accompanied occasionally by neuronal migration defects expressed as either cobblestone lissencephaly or periventricular hypertopia. Here, we report a new case of a TMTC3-related syndrome in a Lebanese family with two affected siblings showing severe psychomotor retardation, intellectual disability, microcephaly, absence of speech, muscular hypotonia, and seizures. Whole exome sequencing revealed a homozygous pathogenic variant c.211 C > T (p.R71C) in the TMTC3 gene in both siblings. A review of the literature on TMTC3-related syndrome and its causal mutations is provided.

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.

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.