Amyotrophic Lateral Sclerosis via the ANG 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 ANG gene have been reported in both AD-FALS and SALS cases (Greenway, M.J. et al. Nat Genet 38(4):411-413, 2006; Paubel, A. et al. Arch Neurol 65(10):1333-1336, 2008; Gellera, C. et al. Neurogenetics 9(1):33-40, 2008). To date, about 25 different causative variants have been reported in ALS patients. Except for one nonsense variant, (c.338G>A, p.W113*) (Lattante, S. et al. Neurology 79(1):66-72, 2012), all of these variants are of the missense type.

ANG mutations appear to be a rare cause of ALS. They account for up to 2.3% of AD-ALS cases and 1% of SALS (Gellera, C. et al., 2008).

Although ANG pathogenic variants have been mostly detected in patients of Irish and Scottish decent, they have been reported in other populations. Specifically, the variant (c.122A>T, p.K41I) has been reported in various populations and appears to be the most common pathogenic ANG variant (Greenway, M.J. et al., 2006). This variant was also reported in all affected members of a Dutch family with a history of ALS. In this family, one of the affected individuals presented with ALS and later developed FTD, while the other affected members had ALS without FTD (van Es, M.A. et al. Neurology 72(3):287-288, 2009).

The ANG gene encodes the angiogenin protein. Mutations in the ANG gene identified in patients with ALS were associated with loss of angiogenic activity (Wu, D. et al. Ann Neurol 62(6):609-617, 2007).

ANG mutations account for up to 2.3% of AD-ALS cases and 1% of SALS (Gellera, C. et al. Neurogenetics 9(1):33-40, 2008).

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

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