Quadruple genetic variants in a sporadic ALS patient

Objectives: Due to upcoming gene-specific therapy approaches for ALS patients, understanding familial and sporadic ALS genetics is becoming increasingly important. In this study, we wanted to investigate underlying genetic causes for an SALS patient.

Methods: We performed ALS gene panel sequencing and subsequent segregation analysis in the family.

Results: Genetic studies suggest that a proportion of SALS cases has an oligogenic origin due to the combination of low-effect size mutations in several ALS genes. Maximally three mutations in different ALS disease genes have been described in isolated ALS patients. Here, we report for the first time the co-occurrence of rare nonsynonymous variants in four known ALS genes in a SALS patient (c.859G > A/p.Gly287Ser in TARDBP, c.304G > T/p.Glu102* in NEK1, c.3446C > A/p.Gly1149Val in ERBB4, and c.1015C > T/p.Arg339Trp in VEGFA). All four variants were unique for the patient, whereas up to three of these variants were detected in the unaffected family members, all older than the patient.

Discussion: Our study suggests that SALS can be caused by the additive or synergistic action of low-effect size mutations. Broader use of gene panel analysis or whole exome/genome sequencing may reveal a potentially treatable oligogenic causation in a higher percentage of SALS than previously thought.