Özet:
Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is characterized by muscle weakness and atrophy due to the degeneration of motor neurons in the motor cortex, brain stem and spinal cord. Both conventional gene discovery methods and association studies helped identify the genetic variants causing several ALS phenotypes. Recently, with the advent of whole exome sequencing (WES), it became possible to sequence the coding regions of the genome for a low cost and in a short time, changing the landscape of genetic disease research, including ALS. Thus, there are more than 40 genes with Mendelian inheritance identified in ALS. However, a significant portion of ALS cases is still genetically unexplained due to the complex genetic background of the disease. In this study, WES was applied to investigate disease-causing variants in a cohort of 57 cases with ALS or other motor neuron diseases. In silico workflow was performed in our laboratory from the raw sequencing data to the final candidate variant lists. Homozygosity mapping was applied to recessively inherited pedigrees. Mutations in 19 distinct genes were identified as the genetic cause in 20 families. Identification of genes causing distal spinal muscular atrophy and neurodegeneration with brain iron accumulation in some cases, suggested controversies between the initial and the final diagnosis of the patients. These findings allowed us to draw two main facts: (i) the complex and heterogeneous nature of ALS and other motor-neuron diseases due to phenotypic overlaps, and (ii) the great success of WES as a current trend in rare disease genetics and differential diagnosis.
