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Neurodegenerative disorders, adult onset v9.25 HSPB1 Eleanor Williams changed review comment from: Removed tags for promotion and expert review for now, as this genes 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.; to: 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.
Neurodegenerative disorders, adult onset v9.25 HSPB1 Eleanor Williams Tag Q3_26_expert_review was removed from gene: HSPB1.
Tag Q3_26_NHS_review was removed from gene: HSPB1.
Tag Q3_26_promote_green was removed from gene: HSPB1.
Neurodegenerative disorders, adult onset v9.22 HSPB1 Eleanor Williams commented on gene: HSPB1
Neurodegenerative disorders, adult onset v9.22 HSPB1 Luke Stuart changed review comment from: 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.

Expert review is recommended 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.; to: 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.
Neurodegenerative disorders, adult onset v9.22 HSPB1 Eleanor Williams Tag Q3_26_NHS_review tag was added to gene: HSPB1.
Neurodegenerative disorders, adult onset v9.22 HSPB1 Eleanor Williams Phenotypes for gene: HSPB1 were changed from Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595 to Neuronopathy, distal hereditary motor, autosomal dominant 3, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Charcot-Marie-Tooth disease axonal type 2F, MONDO:0011687)
Neurodegenerative disorders, adult onset v9.21 HSPB1 Eleanor Williams Publications for gene: HSPB1 were set to 15122254; 28379183
Neurodegenerative disorders, adult onset v9.20 HSPB1 Eleanor Williams Tag Q3_26_expert_review tag was added to gene: HSPB1.
Tag Q3_26_promote_green tag was added to gene: HSPB1.
Neurodegenerative disorders, adult onset v9.20 HSPB1 Eleanor Williams Classified gene: HSPB1 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v9.20 HSPB1 Eleanor Williams Gene: hspb1 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart edited their review of gene: HSPB1: Changed mode of pathogenicity: Other; Changed phenotypes to: 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)
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart edited their review of gene: HSPB1: Changed publications to: 27492805, 17623484, 28797631, 15122254, 27816334
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254). Evidence for a direct association with classical ALS is limited: 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.

Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: 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.

Expert review is recommended 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.
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart edited their review of gene: HSPB1: Changed publications to: 27492805, 17623484, 28797631, 15122254
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: 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 apotential risk mofidiier 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.

The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254). Evidence for a direct association with classical ALS is limited: 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.

Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: 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 apotential risk mofidiier 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.

The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: 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 apotential risk mofidiier 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.

The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.
Neurodegenerative disorders, adult onset v9.15 HSPB1 Luke Stuart reviewed gene: HSPB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27492805, 17623484, 28797631; Phenotypes: Neuropathy, distal hereditary motor, type IIB, OMIM:608634, Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders, adult onset v9.1 HSPB1 Oliver Ziff gene: HSPB1 was added
gene: HSPB1 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: HSPB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPB1 were set to 15122254; 28379183
Phenotypes for gene: HSPB1 were set to Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595
Penetrance for gene: HSPB1 were set to Incomplete
Mode of pathogenicity for gene: HSPB1 was set to Other
Review for gene: HSPB1 was set to GREEN
gene: HSPB1 was marked as current diagnostic
Added comment: 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