Amyotrophic Lateral Sclerosis via the OPTN 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. Over 20 different pathogenic variants in the OPTN gene have been reported in patients with ALS including AD-ALS, SALS and AR-ALS. Initially, both recessive and dominant OPTN mutations were found in Japanese cases of ALS (Maruyama, H. et al. Nature 465(7295):223-226, 2010). Subsequently, dominant mutations were found in European cases including Italian (Del Bo, R. et al. J Neurol Neurosurg Psychiatry 82(11):1239-1243, 2011), Danish (Tümer, Z. et al. Neurobiol Aging 33(1):208.e1-5, 2012), and Canadian (Belzil, W. et al. Neurobiol Aging 32(3):555.e13-4, 2011). Although most mutations are missense, other types were also reported including nonsense, splicing, small deletions or insertions, indels, and large deletions. OPTN mutations account for up to 1.2% of AD-ALS and 3.5% of SALS cases of European descent (Del Bo, R. et al., 2011). To date, recessive mutations were reported in Japanese cases only (Maruyama, H. et al., 2010; Iida, A. et al. Neurobiol Aging 33(8):1843.e19-24, 2012; Iida, A. et al. J Neurol Neurosurg Psychiatry 83(2):233-235, 2012). Of note, based on current data, the OPTN gene does not appear to be involved in FTD or ALS-FTD. Prior to their involvement with ALS, OPTN mutations have been reported in patients with primary open-angle glaucoma and ataxia (POAG) (Rezaie, T. et al. Science 295(5557):1077-1079, 2002). The OTPN gene encodes optineurin protein, which has several roles including transcription activation and membrane trafficking.

OPTN mutations account for up to 1.2% of AD-ALS and 3.5% of SALS cases of European descent (Del Bo, R. et al. J Neurol Neurosurg Psychiatry 82(11):1239-1243, 2011).

Large pathogenic deletions in the OPTN gene have been reported in Japanese ALS cases (Maruyama, H. et al. Nature 465(7295):223-226, 2010; Iida, A. et al. Neurobiol Aging 33(8):1843.e19-24, 2012; Iida, A. et al. J Neurol Neurosurg Psychiatry 83(2):233-235, 2012). However, the proportion of patients with such deletions is unknown at this time.

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