Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease.
OBJECTIVE
To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations.


METHODS
Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center.


RESULTS
Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS.


CONCLUSIONS
A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.
Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
Serena
S
Lattante
Amelia
A
Conte
Marcella
M
Zollino
Marco
M
Luigetti
Alessandra
A
Del Grande
Giuseppe
G
Marangi
Angela
A
Romano
Alessandro
A
Marcaccio
Emiliana
E
Meleo
Giulia
G
Bisogni
Paolo Maria
PM
Rossini
Mario
M
Sabatelli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055815:Young Adult
D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1