Neurodegenerative disorders, adult onset

Gene: SIGMAR1

I don't know

SIGMAR1 is provisionally associated with autosomal recessive Amyotrophic lateral sclerosis 16, juvenile (OMIM:614373) and Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726) (accessed 10/2026). Multiple patients with biallelic variants have been identified, and disease onset is typically in the first decade (Kalita et al. (2025), PMID 41334667; Al-Saif et al. (2011), PMID 21842496, Horga et al. (2016) PMID 27629094). Disruption of Sigmar1 in the mouse leads to locomotor deficit (Bernard-Marissal et al. (2015), PMID 25678561).

Biallelic SIGMAR1 variants typically cause a phenotypic spectrum encompassing juvenile ALS16 and distal hereditary motor neuropathy with pyramidal signs. Recent evidence supports a spectrum of SIGMAR1-related motor neuropathy, with the slowly progressive, distal-predominant phenotype generally favouring dHMN over classical ALS (Yu et al. (2025), PMID 40309037; Kalita et al. (2025), PMID 41334667)).

Adult presentation is documented in isolated cases. Ma et al. (2020), PMID 32600828 reported onset at 34 years in a patient with compound-heterozygous c.247T>C and c.545T>C variants who was referred to an ALS clinic with distal weakness and hyperreflexia; the authors classified the phenotype as dHMN mimicking ALS. An additional Japanese patient developed ALS at 80 years with compound-heterozygous missense variants, though notably, one of the variants (p.R208W) has an allele frequency of 2.9% in East Asians via gnomad v4 and 64 homozygotes across all populations (Izumi et al. (2018), PMID 30311446). Evidence implicating SIGMAR1 in typical adult-onset ALS or ALS–FTD remains disputed (Pickering-Brown et al. (2015), PMID 26088964). SIGMAR1 c.672*51G>T was identified in 3 families with ALS-FTD, though later studies found one of the families also to harbored a C9ORF72 expansion (Luty et al. (2010), PMID 21031579.

As reviewed by Oliver Ziff, despite typical childhood onset, SIGMAR1-related disease can thus present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. NHS England review is ongoing to determine whether SIGMAR1 falls within the intended scope of the adult-onset neurodegenerative disorders panel, based on potential diagnostic utility rather than a definitive association with adult-onset neurodegeneration.

Created: 1 Oct 2026, 2:12 p.m. | Last Modified: 6 Oct 2026, 10:25 a.m.

Panel Version: 9.22

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autosomal recessive amyotrophic lateral sclerosis 16, juvenile (OMIM:614373); Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726); amyotrophic lateral sclerosis type 16 (MONDO:0013715)

Publications

• 41334667
• 21842496
• 27629094
• 25678561
• 40309037
• 32600828
• 30311446
• 26088964
• 21031579

Green List (high evidence)

SIGMAR1 variants are a recognized cause of juvenile and early-adult onset ALS (ALS16) as well as distal hereditary motor neuropathy. Essential for upfront LMN screening to prevent sequential R78 testing after R460.1.

Created: 22 May 2026, 1:08 p.m. | Last Modified: 22 May 2026, 1:08 p.m.

Panel Version: 9.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595

Publications

• 26205306
• 21842496
• 26088964
• 25678561
• 26088963
• 26078401

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Red List (low evidence)

early-childhood onset of a neurologic disorder consistent with juvenile ALS, or Distal spinal muscular atrophy-2 is an autosomal recessive neuromuscular disorder characterized by onset of distal muscle weakness and wasting affecting the lower and upper limbs in the first decade. Both childhood onset - red

Created: 2 Sep 2019, 4:06 p.m. | Last Modified: 2 Sep 2019, 4:06 p.m.

Panel Version: 1.99

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Amyotrophic lateral sclerosis 16, juvenile, 614373

Green List (high evidence)

Includes variants in 3'UTR of gene.

Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.

Panel Version: 1.72

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Amyotrophic lateral sclerosis 16, juvenile, 614373

Publications

• 21842496
• 27821430
• 21031579

Variants in this GENE are reported as part of current diagnostic practice

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11th September 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber

Created: 20 Sep 2019, 4:19 p.m. | Last Modified: 20 Sep 2019, 4:19 p.m.

Panel Version: 1.106

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.

Created: 2 Sep 2019, 4:46 p.m. | Last Modified: 2 Sep 2019, 4:46 p.m.

Panel Version: 1.101

Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.

Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.

Panel Version: 1.74

Review and rating submitted byJames Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.

Created: 23 Apr 2019, 5:35 p.m.

Green List (high evidence)