R. Selvatici, M. Neri, C. Scotton, M. Falzarano, R. Rossi, A. Armaroli, F. Gualandi, S. Fini, A. Ferlini
Neuromuscular Disorders, volume 27, issue 2, pages 194-195
In order to identify novel candidate genes involved in complex neuromuscular phenotypes, within the NEUROMICS project we performed whole genome sequencing (WGS) in: i) 3 patients respectively with : ataxia complicated by spastic paraparesis, ataxia and dystonia, Duchenne-like phenotype. We analyzed the trios in all. ii) 2 families of four, respectively with recurrence in siblings of congenital arthrogryposis and of spastic paraparesis plus ataxia and neuropathy. iii) a sibling pair with limb girdle muscular dystrophy (LGMD) The analysis unraveled the genetic cause of the LGMD: a compound heterozygosis in the CAPN3 gene was identified and validated in both the affected. In the female with a Duchenne-like muscular dystrophy, WGS analysis identified a compound heterozygosis for two missense mutations in the PLEC gene inherited one from each parent. This gene is known to be associated with a peculiar forms of autosomal recessive LGMD. RNA analysis is ongoing. In the patient with ataxia complicated by spastic paraparesis, WGS analysis identified two missense mutations in SPG7 and KIF5A genes not previously described and predicted to be pathogenetic. Segregation analysis in the family showed that the variations were respectively inherited one from the mother and one from the father; both parents are clinically asymptomatic. Therefore we can speculate that the disease is due to the compound heterozygosis identified. In the family with ataxia and dystonia the analysis identified variations in few candidate genes; the variations have been filtered according to the inheritance of the disease, the class of pathogenicity and their functions. All the identified variation will be validated. In the family with congenital arthrogryposis a panel of known disease genes resulted negative and the WGS analysis is still ongoing.