Amyotrophic Lateral Sclerosis/Motor Neuron Disease via the TARDBP 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.

About 50 different pathogenic TARDBP variants have been reported in patients with ALS with or without FTD (Sreedharan, J. et al. Science 319(5870):1668-1672, 2008; Kabashi, E. et al. Nat Genet 40(5):572-574, 2008; Gitcho, M. A. et al. Ann Neurol 63(4):535-538, 2008; Benajiba, l. et al. Ann Neurol 65(4):470-473, 2009). Except for one single nucleotide duplication, (c.1121dupA, p.Y374*), (Daoud, H. et al. J Med Genet 46(2):112-114, 2009), all variants are of the missense type.

TARDBP mutations account for up to 5% of AD-ALS cases (Wijesekera, L.C. and Leigh, P.N. Orphanet J Rare Dis 4:3, 2009) and 2% of SALS (Daoud, H. et al., 2009).

The TARDBP gene encodes the TAR DNA binding protein (TDP-43), an RNA binding protein that is involved in RNA processing.

TARDBP mutations account for up to 5% of AD-ALS cases (Wijesekera and Leigh, P.N. Orphanet J Rare Dis 4:3, 2009) and 2% of SALS (Daoud et al. J Med Genet 46(2):112-114, 2009).

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

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