👤 Sandra Sabbagh

Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. 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. 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. Show less

Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding cardiac sarcomere proteins. Nowadays genetic testing of HCM plays an important role in clinical practice by contributing to the diagnosis, prognosis, and screening of high-risk individuals. The aim of this study was developing a reliable testing strategy for HCM based on linkage analysis and appropriate for Iranian population. Six panels of four microsatellite markers surrounding MYH7, MYBPC3, TNNT2, TNNI3, TPM1, and MYL2 genes (24 markers in total) were selected for multiplex PCR and fragment length analysis. Characteristics of markers and informativeness of the panels were evaluated in 50 unrelated Iranians. The efficacy of the strategy was verified in a family with HCM. All markers were highly polymorphic. The panels were informative in 96-100% of samples. Multipoint linkage analysis excluded the linkage between the disease and all six genes by obtaining maximum LOD score ≤-2. This study suggests a reliable genetic testing method based on linkage analysis between 6 sarcomere genes and familial HCM. It could be applied for diagnostic, predictive, or screening testing in clinical setting. Show less

VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect. Show less