RESUMEN
SOD1, ANG, TARDBP and FUS mutations have been associated with amyotrophic lateral sclerosis (ALS). Our goal was to extend molecular genetic analysis to newly identified ALS genetic loci and to determine the frequency of mutations, distribution of disease genes, and variant spectrum of these genes in a large United States ALS-phenotype cohort. We screened 1220 probands with an ALS phenotype, referred originally for SOD1 molecular genetic analysis. 1128 SOD1-negative probands were screened for ANG, and 277 and 223 SOD1- and ANG-negative samples were screened for TARDBP and FUS, respectively. One hundred additional probands were specifically screened only for FUS exon 15. We identified a total of 36 different SOD1 mutations, including three novel mutations, in 92 probands. ANG screening identified three mutations, including two novel mutations, and TARDBP screening identified two previously reported TARDBP mutations. We also identified four mutations in FUS, including the reported FUS in-frame deletion, c.430_447del, p.Gly144_Tyr149del, in a patient with inclusion body myositis, and two known FUS missense mutations. From this study, we estimate frequencies for SOD1, ANG, TARDBP and FUS mutations, in this United States cohort, to be 7.5%, 0.71%, 0.72% and 1.9%, respectively. In conclusion, we identify novel variants in SOD1, ANG, TARDBP and FUS, and expand the FUS-associated clinicopathologic phenotype.
