Open AccessQuadruple genetic variants in a sporadic ALS patient
Author(s) -
Yilmaz Rüstem,
Weishaupt Kanchi,
Valkadinov Ivan,
Knehr Antje,
Brenner David,
Weishaupt Jochen H.
Publication year - 2022
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1953
Subject(s) - nonsynonymous substitution , genetics , exome sequencing , gene , biology , mutation , exome , whole genome sequencing , genetic heterogeneity , disease , genome , medicine , phenotype , pathology
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.