TABLE 1.

Genes linked to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Paget’s bone disease (PBD), inclusion body myopathy (IBM) and multi-system proteinopathy (MSP).

Gene	Chromosome Locus	Gene product	Clinical presentation	Pathological subtype	Typical inclusion subtype	Relevant pathological regions as described in early publications	References
TARDBP	1p36	TAR DNA Binding Protein 43	ALS	ALS-TDP	TDP-43-positive NCIs, NIIs, DNs, GCIs as well as Bunina bodies.	Spinal cord, motor cortex, throughout all cortical layers, dentate granule cells of the hippocampus.	Sreedharan et al., 2008
C9ORF72	9q21-22	Chromosome 9 open reading frame 72	ALS/FTD	ALS-TDP	Many TDP-43 positive NCIs, some DNs; rare cases with many long corkscrew DNs or with many NCIs, DNs and some NIIs.y TDP-43-negative star-shaped NCIs, DPR positive, ubiquitin-positive and p62-positive.	TDP-43-positive inclusions in hippocampus, including the granule layer of the dentate gyrus, and CA4 sub region; throughout the cerebellar cortex, neocortex, cerebellar granule cells. DPR inclusions throughout the CNS, most reliably in CA3 and CA4 of hippocampus.	DeJesus-Hernandez et al., 2011; Renton et al., 2011; Lashley et al., 2015
SOD1	21q22	Superoxide dismutase 1	ALS	ALS-SOD1	SOD1-positive, TDP-43-negative NCIs Neurofilament-positive, SOD1-negative HCIs in some genotypes.	Spinal cord	Rosen et al., 1993
FUS	16q12.1-q12.2	Fused in Sarcoma	ALS	ALS-FUS	FUS-positive, TDP-43-negative NCIs and GCIs with highly variable morphology including small bean-shaped and large annular shaped or elongated globular inclusions. Occasional NIIs and DNs	Spinal cord, motor cortex, cerebral cortex, medial temporal lobe, subcortical and brainstem nuclei, basal ganglia.	Vance et al., 2009
OPTN	10p13	Optineurin	ALS	ALS-TDP	Inclusions that are positive for optineurin, ubiquitin, and TDP-43 as NCIs including skein-like inclusions and round hyaline inclusions	Spinal cord including corticospinal tracts and anterior horn	Maruyama et al., 2010
VCP	9p13	Valosin Containing Protein	ALS ALS/FTD FTD PBD IBM MSP	ALS-TDP	Numerous TDP-43-positive NIIs, DNs and some NCIs., Bunina bodies	Muscle fibers, spinal cord anterior horn, brainstem	Johnson et al., 2010; Mehta et al., 2013; Lashley et al., 2015
UBQLN2	Xp11-q12	Ubiquilin 2	ALS ALS/FTD	ALS-TDP	Skein-like or small round TDP-43-positive NCIs, with some larger inclusions of up to 20 μm	Spinal cord, hippocampus including the dentate granule cells and sub regions CA1 and CA3, neuropil and molecular layer of the cerebellar cortex	Deng et al., 2011
SQSTM1	5q35.3	Sequestosome 1	ALS-TDP FTD PBD IBM MSP	ALS-TDP	TDP-43- and p62-positive and NCIs including skein-like inclusions, spherical inclusions including Lewy body-like inclusions and basophilic inclusions, small dot-like ubiquitin positive granules and some larger ‘seed like’ NCIs. Thin DNs, numerous Bunina bodies, GCIs	Anterior horn of the spinal cord, cortical layer 2, temporal cortex, entorhinal cortex, granule cells in dentate gyrus of the hippocampus	Arai et al., 2003; Mizuno et al., 2006; Fecto et al., 2011; Teyssou et al., 2013
TBK1	12q14.2	TANK-binding kinase 1	ALS FTD	ALS-TDP	Perinuclear TDP-43-positive NCIs and short DNs, NFT-like inclusions, GCIs and some tufted astrocytes	Ventral horn of the cervical and thoraco-lumbar spinal cord, all layers of frontal and temporal neocortex, para-hippocampal gyrus and dentate gyrus, entorhinal cortex, neostriatum and the pallidum	Freischmidt et al., 2015; Van Mossevelde et al., 2016
CHMP2B	3p12	Chromatin modifying protein 2B	ALS FTD	ALS-TDP	In FTD cases, TDP-43-negative NCIs, DNs and coiled body type inclusions, GCIs. In cases with an ALS presentation, TDP-43 positive, ubiquitin positive NCIs and GCIs	Throughout the frontal cortex, motor and pre-motor cortex, dentate gyrus of the hippocampus in FTD presentation? In ALS presentation: spinal cord motor neurones, motor cortex	Parkinson et al., 2006; Cox et al., 2010
hnRNPA1	12q13.13	Heterogeneous nuclear ribonucleoprotein A1	ALS FTD PBD IBM MSP	ALS-TDP	Rimmed vacuoles and atrophic fibers, cytoplasmic inclusions in muscle. In brain, TDP-43 positive skein-like NCIs	Muscle cells, spinal cord, motor cortex, throughout all cortical layers, dentate granule cells of the hippocampus	Kim et al., 2013
ANAX11	10q22.2	Annexin A11	ALS FTD MSP	ALS-TDP	Numerous TDP-43-positive NCIs, including skein-like, filamentous and large tubular shaped inclusions, abundant torpedo-like neuritic structures	Anterior horn of the spinal cord, corticospinal tracts, motor cortex, neuropil, dentate gyrus of the hippocampus, temporal neocortex, occipital lobe	Smith et al., 2017

Pathological inclusions include neuronal cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), dipeptide-repeat (DPR), hyaline conglomerate inclusions (HCIs), neuronal intranuclear inclusions (NIIs), and glial cytoplasmic inclusions (GCIs).