Neurodegenerative disorders, adult onset

Gene: HSPB1

Removed tags for promotion and expert review for now, as this gene is part of a set of genes that clinically mimics progressive muscular atrophy, which will be part of a larger review of the panel content.

Created: 6 Oct 2026, 3:19 p.m. | Last Modified: 7 Oct 2026, 1:18 p.m.

Panel Version: 9.25

I don't know

Variants in HSPB1 are a recurrent and established cause of distal Hereditary Motor Neuropathy (dHMN), and are associated with Charcot-Marie-Tooth disease, axonal, type 2F (CMT2F, OMIM:606595) and Neuronopathy, distal hereditary motor, autosomal dominant 3 (OMIM:608634) (accessed 10/2026). In a cohort of 301 individuals with CMT and 115 with distal hereditary motor neuropathy, a segregating HSPB1 missense variant was identified in a Russian CMT2F family, with four additional missense variants found across four distal-HMN families; mutant HSPB1 reduced neuronal-cell viability and disrupted neurofilament assembly (Evgrafov et al., (2004), PMID 15122254). As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease- in a natural history study of HSBP1 neuropathy, patients developed adult-onset progressive weakness, wasting and chronic denervation (Rossor et al. (2016), PMID 27816334.

Evidence for a direct association with classical ALS is limited and equivocal: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection.

NHS England review is ongoing to determine whether HSPB1 should be included in the adult onset neurodegenerative disorders panel to capture patients with HSPB1-related neuropathy who clinically mimic progressive muscular atrophy or motor neuron disease, rather than as an established cause of motor neuron disease.

Created: 30 Sep 2026, 3:05 p.m. | Last Modified: 6 Oct 2026, 10:39 a.m.

Panel Version: 9.22

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Charcot-Marie-Tooth disease axonal type 2F (MONDO:0011687)

Publications

• 27492805
• 17623484
• 28797631
• 15122254
• 27816334

Mode of pathogenicity
Other

Green List (high evidence)

HSPB1 variants (typically toxic gain-of-function missense mutations) frequently present with a late-onset, progressive lower motor neuron phenotype that clinically mimics progressive muscular atrophy (PMA) and ALS. Adding this target to the Adult onset neurodegenerative disorder component panel is necessary to capture these LMN mimics upfront on WGS requests for suspected MND (R460.1), preventing sequential and costly WGS reanalysis requests for the neuropathy panel (R78).
Sources: Expert Review, Literature

Created: 22 May 2026, 12:57 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

• 15122254
• 28379183

Mode of pathogenicity
Other

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