GENETIC ANALYSIS OF CHARCOT-MARIE-TOOTH DISEASE IN THE POPULATION OF QATAR.

Abstract

Background: Charcot-Marie-Tooth (CMT) disease represents a group of inherited neurological disorders characterized by chronic motor and sensory neuropathy that causes several symptoms such as, progressive muscle weakness, foot deformities, and peripheral neuropathy. CMT has a worldwide prevalence of approximately 1 in 2,500 individuals. Aim: This study aims to investigate the genetic basis of CMT disease in the population of Qatar, evaluate the diagnostic yield of various genetic testing methods utilized in Qatar, and explore the genotype-phenotype correlations among patients diagnosed with CMT. Methodology: A retrospective chart review was conducted on 25 adult patients diagnosed with CMT who were seen at the Medical Genetics Department at Hamad Medical Corporation (HMC), Qatar, between January 2015 and May 2024. All included patients underwent genetic testing, including chromosomal microarray analysis (CMA), multi-gene panel testing, or whole exome sequencing (WES). Results: The overall diagnostic yield of genetic testing for CMT in this cohort was 68%. Among the individual testing methods, WES had the highest diagnostic yield at 60%, followed by CMA at 42%, and CMT panel testing at 33%. A total of 17 cases were classified as genetically confirmed CMT. A total of 17 cases were classified as positive cases with a genetic diagnosis of CMT. Three cases were found to have variants of uncertain significance (VUSs). The re-evaluation of these VUSs resulted in the consideration of one variant as being pathogenic and contributing to the phenotype seen in patient, therefore, the case was re-categorized as positive. We also identified the two most common genes associated with CMT in Qatar as being the SORD gene, followed by the PMP22 gene. The most common clinical feature among genetically confirmed CMT patients was progressive lower limb weakness, seen in 16 out of 17 individuals, followed by neuropathy in 11 patients and foot drop in 7. Less frequent features included pes cavus, hammer toes, hearing loss, tremors, balance issues, burning sensations, and hand clawing, each observed in only a few patients Conclusion: This study represents the first genetic analysis of CMT in Qatar and highlights SORD as a potential first-tier target for genetic testing in Qatari families. Our findings also support the use of WES as a follow-up test after negative initial genetic testing, given its high diagnostic yield. This approach may improve diagnostic efficiency while minimizing unnecessary costs and use of resources.