Amyotrophic lateral sclerosis (AML) is a rare and progressive neurological disease. It hinders voluntary movements like talking, chewing, and walking. This study aims to assess the disease phenotype and familial clustering in ALS cases to determine the role of pathogenic genes.

The study included a total of 253 French familial ALS (FALS). A next-generation, targeted sequence analysis was conducted on them. The mutations in 30 disease-linked genes got identified using the unrelated probands. The number of ALS cases and generations got analyzed. Other genealogical factors like age, gender, site of onset, and disease duration were also important parameters.

A total of 49 pedigrees had only 1 affected generation. The two and three affected generations were 152 and 34 in number, respectively. 98 cases had an abnormal G4C2 expansion in the C9orf72 among 149 pedigrees (or 63.4%) with a deleterious variant. The SOD 1, FUS, and TARBP mutations were found in 30, 7, and 9 cases, respectively. The G4C2 abnormality has a higher frequency in pedigrees with affected ALS pair of cases at 65.2%. All pedigrees had SOD 1, but monogenerational pedigrees did not have FUS and TARBP. Bigenerational pedigrees with a minimum of 3 cases had TARBP, while 7 cases in multigenerational pedigrees had FUS with onset age less than 43 years.

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Phenotypes, genotypes, and familial clustering are interconnected in FALS. The familiar genetic screening and ALS cases phenotypes can be targeted.

Ref: https://jnnp.bmj.com/content/early/2021/01/06/jnnp-2020-325064