Comprehensive genetic characterization of an Argentinian cohort with amyotrophic lateral sclerosis

SCHOTTLAENDER, LUCIA V.; MORGAN, SARAH; SHOAI, MARYAM; O'CONNOR, EMER; HARDY, JOHN; HOULDEN, HENRY; REISIN, RICARDO; PITTMAN, ALAN

London

Congreso; UK Neuromuscular Translational Research Conference; 2017

MRC neuromuscular centre

Background and aimsThe Argentinian population presents a heterogeneous genetic makeup, composed by a 65% of Europeans, a 31% of Indigenous Americans and a 4% of Africans. Genetic studies and, in particular next generation sequencing technologies (NGS), have disproportionally examined the genetics of western and Asian populations over African and South American individuals. This extends to diseases like amyotrophic lateral sclerosis (ALS) where recently, the C9orf72 expansion was detected in 2% of sporadic and 1of 3 families in a series of ALS cases from Argentina, but other ALS-causing genes remain unexplored. Hence, the motivation of this study.MethodsTwenty-six Argentinian patients with a clinical diagnosis of ALS were scrutinised for disease-causing variation by fragment analysis and targeted NGS. ResultsThirteen patients harboured 14 rare potentially pathogenic alterations in the genes SOD1, TARDBP, FUS, UBQLN2, VCP, CHMP2B, SETX, ATXN2 and C9orf72. However, when we Sanger sequenced the variants detected by NGS, only 8 out of 12 could be confirmed, and after genetic analysis, one variant in FUS and one variant on SETX were considered most likely non-pathogenic. There were 5 previously reported missense mutations in SOD1 (p.G86S and p.D84G), VCP (p.R155H), TARDBP (p.N378D), UBQLN (p.497S) and 2 C9orf72 repeat expansions. There was one novel alteration in CHMP2B (p.R32Q). This variant, found in a subject with a family history of ALS, is predicted to be damaging by Polyphen and mutation taster, but tolerated by SIFT. Segregation could not be studied due to lack of samples so this variant is currently considered of unknown pathogenicity. Three intermediate ATXN2 repeats of 27 counts were found in 3 subjects exhibiting other concomitant ALS variants mentioned above in the genes TARDBP, UBQLN and CHMP2B. To sum up, the total detected pathogenic ALS mutation rate was of 27%, which accounts for 63% among familial and 12% among sporadic subjects. ConclusionThese results provide evidence that Argentinian populations have a similar genetic landscape for ALS as Europeans. Moreover, new genetic technologies, in particular NGS, have proven to be cost effective methods for screening of genetic variation. However, the gold standard for mutation confirmation remains to be Sanger sequencing.