Genotype-phenotype correlation in Tunisian patients with Amyotrophic Lateral Sclerosis

• DOI: 10.1016/j.neurobiolaging.2022.08.002
• Publication Date: 2022-08-14T21:30:12Z
• Authors: Imen Kacem; Ikram Sghaier; Silvia Peverelli; Emira Souissi; Nicola Ticozzi; Alya Gharbi; Antonia Ratti; Amina Gargouri Be...; Vincenzo Silani; Riadh Gouider
• Keywords: 0301 basic medicine; 03 medical and health sciences; Superoxide Dismutase-1; C9orf72 Protein; Amyotrophic Lateral Sclerosis; Humans; Neurodegenerative Diseases; Amyotrophic Lateral Sclerosis (ALS); Genetics; Phenotype; TARDBP; Tunisia-Africa;; Genetic Association Studies; 3. Good health

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. To date, mutations in more than 30 genes have been linked to familial ALS forms. However, no mutational screenings have been reported in African populations so far. We aimed to investigate the presence of rare genetic variants in the 4 most common ALS causative genes among a Tunisian cohort. Patients were screened for mutations in SOD1 (exons 1-5), TARDBP (exon 6), FUS (exons 5, 6, 13/14, and 15). Juvenile ALS (JALS) patients were screened also for ALS2 (exons 3, 10, 28). Analysis of C9ORF72 was conducted by fluorescent amplicon-length analysis and repeat-primed PCR. We analyzed 197 Tunisian ALS patients, including 11 familial forms (fALS) with 17 ALS cases, 167 sporadic (sALS) and 13 JALS cases. The pathogenic variant TARDBP p.G294A mutation was reported among 18 patients. Repeat expansion in C9orf72 was recorded in 9 patients. Interestingly, 2 unrelated patients carried a double mutation in both C9orf72 and TARDBP genes. Finally, the p.Asp91Val mutation in SOD1 was identified among 4 cases in homozygous state including 3 sALS and 1 familial JALS with recessive inheritance. No pathogenic variants in FUS were identified, nor ALS2 variants in JALS cases. In our Tunisian cohort the most frequently mutated gene is TARDBP (9.4%), followed by C9orf72 (3.9%) and SOD1 (2.1%). Our study broadens the mutational spectrum in patients with ALS and defines for the first time the mutational frequency of the main ALS genes in patients of African ethnicity.