Amyotrophic Lateral Sclerosis (ALS) via the hnRNPA1 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 and Bradley 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 and Rothstein 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 et al. 1982; Lipton, et al. 2004; Mitsuyama and Inoue 2009).

About 10% of ALS cases are familial (Emery and Holloway 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 2012).

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. Several genes have been implicated in the disease including C9orf72, SOD1, FUS, TARDBP, ANG, OPTN, VCP, VAPB, and PFN1.

Recently, two heterozygous missense variants in the hnRNPA1 gene were identified, by whole exome sequencing, in patients with ALS. The first, (c.940G>A, p. Asp314Asn), occurred in one family with a history of autosomal dominant ALS and no pathogenic variants in the known ALS genes (Kim et al. 2013). Evidence for pathogenicity included its co-segregation with the disease; its absence from the NHLB1 Exome Sequencing Project; its location in an evolutionary conserved region of the protein; and a predicted deleterious effect by PolyPhen. The second variant, (c.956A>G, p.Asn319Ser), occurred in a sporadic case, and was reported as probably pathogenic (Kim et al. 2013).

The heterogeneous nuclear ribonucleoprotein hnRNPA1 is involved in mRNA metabolism through interactions with TDP-43, which is known to be involved in the pathogenesis of ALS (Buratti et al. 2005). Pathological studies revealed reductions of hnRNPA1 protein level accompanied by an aggregation of TDP-43 in motor neurons of spinal cord samples from autopsied patients with ALS, compared to that of controls (Honda et al. 2015)

Pathogenic variants in the hnRNPA1 gene appear to be a rare cause of ALS. To date, only two missense variants have been reported in patients with ALS; one of which is reported as probably pathogenic (Kim et al. 2013). More recent studies confirmed the earlier findings. No pathogenic HNRNPA1 variants were identified among Dutch and French cohorts of patients with ALS and ALS-FTD, with no causative variants in the remaining ALS genes (Seelen et al. 2014; Le Ber et al. 2014).

This test provides full coverage of all coding exons of the hnRNPA1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.