Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the FUS Gene

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain steam, and spinal cord (Tandan, R. and Bradley, W.G. Ann Neurol 18(3):271-280, 1985). The dysfunction and loss of these neurons results in rapid progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. The mean age of onset of symptoms is about 55 years of age; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 1-2 per 100,000 (Cleveland, D.W. and Rothstein, J.D. Nat Rev Neurosci 2(11):806-819, 2001). The most common symptoms include twitching and cramping of muscles of the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty in talking, breathing and swallowing, shortness of breath, and paralysis. Cognitive impairment has not been initially associated with ALS. However, frontotemporal dementia (FTD) has been reported in several cases. Dementia has been documented in patients with ALS from different ethnic groups and affects both males and females (Wikström, J. et al. Arch Neurol 39(11):681-683, 1982; Lipton, A.M. et al. Acta Neuropathol 108(5):379-385, 2004; Mitsuyama, Y. and Inoue, T. Neuropathology 29(6):649-654, 2009).

About 10% of ALS cases are familial (Emery, A.E. and Holloway, S. Adv Neurol 36:139-147, 1982). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and is age-dependent with high penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern. About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. It is unclear how many of the apparently sporadic cases are inherited with low penetrance. The clinical presentations of familial ALS (FALS) and sporadic ALS (SALS) are similar. However, the onset of symptoms in FALS is usually earlier compared to that of SALS (Kinsley and Siddique. GeneReviews, 2012). Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. At least twelve genetic loci have been reported. Several genes have been identified and include C9orf72, SOD1, FUS, TARDBP, ANG and OPTN. Pathogenic variants in the FUS gene have been reported in patients with ALS (Kwiatkowski, T.J., Jr. et al. Science 323(5918):1205-1208, 2009; Vance, C. et al. Science 323(5918):1208-1211, 2009), and account for up to 4% of AD-ALS cases and 2% of SALS (Hewitt, C. et al. Arch Neurol 67(4):455-61, 2010). About 70 different FUS pathogenic variants have been reported to date. Although most variants are missense resulting in amino acid substitutions, splicing and nonsense variants, as well as small deletions and insertions have been reported. The latter include both frame-shift and in-frame mutations. To date, no pathogenic regulatory variants or large deletions in the FUS gene were reported to be the cause of ALS. All FUS causative variants were heterozygous, except for the H517Q variant, which was found in the homozygous state in four patients from a consanguineous family of Cape Verdean origin (Kwiatkowski, T.J., Jr. et al, 2009). The FUS gene encodes the FUS (fused in sarcoma) protein, which has been involved in several cellular processes including transcription regulation and alternative splicing.

This test allows the detection of mutations in up to 4% of AD-ALS cases and 2% of SALS (Hewitt, C. et al. Arch Neurol 67(4):455-461, 2010).

Thus far, no pathogenic gross deletions or duplications have been reported in the FUS gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the FUS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.