Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease that affects motor neurons, leading to paralysis and death usually 3-5 years after the onset of symptoms. The investigation of both sporadic and familial ALS highlighted four main genes that contribute to the pathogenesis of the disease: SOD1, FUS, TARDBP and C9orf72. This study aims to provide a comprehensive investigation of genetic variants found in SOD1, FUS and TARDBP genes in Greek sporadic ALS (sALS) cases. Our sequencing analysis of the coding regions of the abovementioned genes that include the majority of the variants that lead to ALS in 32 sALS patients and 3 healthy relatives revealed 6 variants in SOD1, 19 variants in FUS and 37 variants in TARDBP, of which the SOD1 p.D90A and the FUS c.*356G>A (rs886051940) variants have been previously associated with ALS, while two novel nonsense pathogenic variants were also identified, namely FUS p.R241* and TDP-43 p.Y214*. Our study contributes to the worldwide effort toward clarifying the genetic basis of sALS to better understand the disease's molecular pathology.

Keywords: FUS; SOD1; TARDBP; amyotrophic lateral sclerosis; genetics; genomic variants; sporadic ALS.

Figure 1

Inheritance tree diagrams of three patient–healthy relative pairs show the inheritance pattern of FUS variants. (a) Variant c.264A>G was found in healthy individual ALS-59, but not patient ALS-58. (b) Variants c.184G>C and c.221G>T were found in patient ALS-66 but not in their healthy daughter ALS-67. (c) Variants c.*356G>A and c.*446G>A were found in healthy individual ALS-71, but not in patient ALS-72.

Figure 2

Inheritance tree diagrams of three patient–healthy relative pairs show the inheritance pattern of TARDBP variants. Bold indicates variants inherited from an ALS patient to healthy offspring. (*) indicate variants that are common in patients but not in healthy individuals.