Amyotrophic Lateral Sclerosis via the UBQLN2 Gene

Amyotrophic lateral sclerosis (ALS, OMIM 105400), is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain stem, and spinal cord (Tandan and Bradley, Ann Neurol 18:271-280, 1985). The dysfunction and loss of these neurons result 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 and Rothstein, Nat Rev Neurosci 2:806-819, 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, fatigue, tripping, and falling. Although cognitive impairment is not usually associated with ALS, frontal lobe dementia has been reported in rare cases. Dementia in ALS cases occurs in patients from different ethnic groups and affects both males and females (Wikström et al. Arch Neurol 39:681-683, 1982; Lipton et al. Acta Neuropathol 108:379-385, 2004; Mitsuyama and Inoue Neuropathology 29:649-654, 2009). 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.

About 10% of ALS cases are familial (Emery and Holloway Adv Neurol 36:139-147, 1982). In most of these families, ALS is inherited in an autosomal dominant (AD-ALS) manner. In rare families, the disease is transmitted with an autosomal recessive pattern (AR-ALS). 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. Five genes have been previously associated with the typical from of ALS, including AD-ALS and SALS (SOD1, FUS, TARDBP, ANG, and OPTN) and two genes with AR-ALS (ALS2 and OPTN). Recently, five UBQLN2 missense variants were reported in five unrelated ALS families with or without dementia. In these families, the disease is inherited in an X-linked dominant manner. Onset of symptoms varies between 16 and 71 years of age, with an earlier onset in male patients. Dementia is not present in all related patients with the same UBQLN2 variant (Deng et al. Nature 477:211-215, 2011). The ubiquilin 2 protein is a member of the ubiquitin-like protein family, which is involved in in vivo protein degradation in the proteasome.

Unknown at this time.

This test provides full coverage of all coding exons of the UBQLN2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).