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| Neurodegenerative disorders, adult onset v9.22 | HSPB8 |
Luke Stuart changed review comment from: As reviewed by Oliver Ziff, HSPB8-related disease may present in adulthood or enter an adult lower motor neuron (LMN) disease or progressive muscular atrophy (PMA) diagnostic pathway because of overlapping clinical presentation (Putko et al. (2025) PMID 41426051)). NHS England review is ongoing to determine whether HSPB8 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.; to: HSPB8 is associated with Charcot-Marie-Tooth disease, axonal, type 2L (OMIM:608673); Myopathy, myofibrillar, 13, with rimmed vacuoles (OMIM:621078); Neuronopathy, distal hereditary motor, autosomal dominant 2 (OMIM:158590) (accessed 10/2026). As reviewed by Oliver Ziff, HSPB8-related disease may present in adulthood or enter an adult lower motor neuron (LMN) disease or progressive muscular atrophy (PMA) diagnostic pathway because of overlapping clinical presentation (Putko et al. (2025) PMID 41426051)). NHS England review is ongoing to determine whether HSPB8 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. |
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| 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. |
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| Neurodegenerative disorders, adult onset v9.22 | SIGMAR1 |
Luke Stuart changed review comment from: 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. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than in relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration.; to: 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. |
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| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. The gene is therefore proposed for green rating. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility.; to: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. This gene is therefore proposed for green rating on this panel in the next GMS update. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review from GLHs is therefore sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility.; to: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. The gene is therefore proposed for green rating. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review from GLHs is therefore sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | SIGMAR1 |
Luke Stuart changed review comment from: 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. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than on relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration.; to: 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. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than in relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration. |
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| 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. |
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| 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. |
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| 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. |
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| Neurodegenerative disorders, adult onset v9.9 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:33581934 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. Sources: Literature |
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| Neurodegenerative disorders, adult onset v8.19 | ISCA-37478-Loss | Arina Puzriakova edited their review of Region: ISCA-37478-Loss: Added comment: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v8.19 | ISCA-37446-Loss | Arina Puzriakova changed review comment from: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing. Other regions that were previously removed should also be reviewed. ; to: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v8.19 | ISCA-37446-Loss | Arina Puzriakova commented on Region: ISCA-37446-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v8.19 | ISCA-37446-Loss | Arina Puzriakova changed review comment from: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.; to: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing. Other regions that were previously removed should also be reviewed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v8.18 | ISCA-37446-Loss | Arina Puzriakova commented on Region: ISCA-37446-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v7.14 | SGIP1 | Arina Puzriakova Added comment: Comment on publications: PMID:39332416 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v7.10 | POLG | Sarah Leigh Added comment: Comment on publications: PMID: 39498811 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v7.7 | NOP56_GGCCTG | Arina Puzriakova edited their review of STR: NOP56_GGCCTG: Added comment: After GMS expert consideration, the rating of this STR has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v6.5 | ATXN2_CAG | Sarah Leigh commented on STR: ATXN2_CAG: The rating of this entity has been updated to green following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v6.5 | ATXN7_CAG | Sarah Leigh commented on STR: ATXN7_CAG: The rating of this entity has been updated to green following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v6.4 | NAA60 | Sarah Leigh commented on gene: NAA60: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | SS18L1 | Sarah Leigh changed review comment from: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | SS18L1 | Sarah Leigh edited their review of gene: SS18L1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | SPG7 | Sarah Leigh commented on gene: SPG7: The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | SPG21 | Sarah Leigh edited their review of gene: SPG21: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | PSAP | Sarah Leigh edited their review of gene: PSAP: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | NEK1 | Sarah Leigh edited their review of gene: NEK1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | GBE1 | Sarah Leigh edited their review of gene: GBE1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.37 | DNAJB2 | Sarah Leigh edited their review of gene: DNAJB2: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v4.22 | PSAP | Sarah Leigh edited their review of gene: PSAP: Added comment: Associated with Parkinson disease 24, autosomal dominant, susceptibility to (OMIM:619491), but not associated with the same condition in Gen2Phen. PMID: 32201884 reports three PSAP variants in three unrelated families with OMIM:619491. Supportive in vitro functional studies were also presented for the reported variants. However, it would appear that there maybe variable expressivity or incomplete penetrance of the Parkinson phenotype, as two variant carrying sibs in Family 2 had extrapyramidal signs, but did not have the full Parkinsons phenotype (PMID: 32201884).; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v3.49 | CLCN2 | Arina Puzriakova commented on gene: CLCN2: The mode of inheritance of this gene has been updated to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v3.49 | XK | Arina Puzriakova edited their review of gene: XK: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.277 | XK | Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next major review. Neurodegenerative component resembling Huntington disease becomes apparent in older individuals. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.275 | GBA | Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.274 | SLC52A3 | Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' as I could not identify evidence supporting relevance of heterozygous variants in disease. This is consistent with the MOI in OMIM/G2P and other PanelApp panels. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.268 | ISCA-37468-Loss | Arina Puzriakova commented on Region: ISCA-37468-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.268 | ISCA-37404-Loss | Arina Puzriakova commented on Region: ISCA-37404-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.263 | FIG4 | Sarah Leigh commented on gene: FIG4: The rating of this gene has been updated following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.263 | ERBB4 | Sarah Leigh commented on gene: ERBB4: The rating of this gene has been updated following NHS Genomic Medicine Service approval. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.48 | APP | Ivone Leong Phenotypes for gene: APP were changed from Alzheimer disease 1, familial OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants OMIM:605714 to Alzheimer disease 1, familial, OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, OMIM:605714 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.38 | APP | Sarah Leigh Phenotypes for gene: APP were changed from Clinical syndrome Alzheimer disease; Dementia to Alzheimer disease 1, familial OMIM:104300; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants OMIM:605714 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v2.16 | DNAJC7 |
Zornitza Stark gene: DNAJC7 was added gene: DNAJC7 was added to Neurodegenerative disorders - adult onset. Sources: Literature Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DNAJC7 were set to https://doi.org/10.1212/NXG.0000000000000503 Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis Review for gene: DNAJC7 was set to AMBER Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. No segregation or functional data. A small number of individuals with LOF variants are present in gnomad albeit less than expected. Given these are cohort studies, and an adult-onset condition, potentially of variable penetrance, we have taken a cautious approach and rated Amber for now but would be interested in other expert opinions. No PMID yet. Sources: Literature |
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| Neurodegenerative disorders, adult onset v2.3 | APP | alisdair mcneill reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.117 | TAF1 | Louise Daugherty changed review comment from: Comment on list classification: Prior to GLH sign off for this panel, TAF1 was discussed further by the specialist test group. It was raised by WWMGLH that the gene should be downgraded from Green to Red as they were not sure if the pipeline could detect the alu-like insertion variant - and no other variants reported in HGMDPro in association with Dystonia-Parkinsonism. However, further correspondence from LNGLH Huw Morris suggested Amber rating - as per movement disorders on PanelApp. Noting that the genetic aetiology of this disorder is complex and not fully understood; to: Comment on list classification: Prior to GLH sign off for this panel, TAF1 was discussed further by the specialist test group. It was raised by WWMGLH that the gene should be downgraded from Green to Red as they were not sure if the pipeline could detect the alu-like insertion variant - and no other variants reported in HGMDPro in association with Dystonia-Parkinsonism. However, further correspondence from LNGLH Huw Morris suggested an Amber rating - as per movement disorders on PanelApp. Noting that the genetic aetiology of this disorder is complex and not fully understood. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.117 | TAF1 | Louise Daugherty Added comment: Comment on list classification: Prior to GLH sign off for this panel, TAF1 was discussed further by the specialist test group. It was raised by WWMGLH that the gene should be downgraded from Green to Red as they were not sure if the pipeline could detect the alu-like insertion variant - and no other variants reported in HGMDPro in association with Dystonia-Parkinsonism. However, further correspondence from LNGLH Huw Morris suggested Amber rating - as per movement disorders on PanelApp. Noting that the genetic aetiology of this disorder is complex and not fully understood | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.102 | MARS | Louise Daugherty commented on gene: MARS: Added new-gene-name tag, new approved HGNC gene symbol for MARS is MARS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.102 | AARS | Louise Daugherty commented on gene: AARS: Added new-gene-name tag, new approved HGNC gene symbol for AARS is AARS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.102 | DARS | Louise Daugherty commented on gene: DARS: Added new-gene-name tag, new approved HGNC gene symbol for DARS is DARS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.101 | APP | Louise Daugherty commented on gene: APP: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.100 | APP | Louise Daugherty Source Wessex and West Midlands GLH was added to APP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.99 | OPHN1 | Tracy Lester reviewed gene: OPHN1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.99 | APP | Tracy Lester reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Clinical syndrome Alzheimer disease, Dementia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.81 | PRKRA | Louise Daugherty Publications for gene PRKRA were changed from 18420150 - a novel heterozygous variant c.266_267delAT; 25914261; 26990861; 22842711; 24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation; 25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism; 22842711 describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa; 18243799; 25142429; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 18420150; p.H89fsX20 was reported in a proband with early childhood-onset leg dystonia (though testing in the parents was not mentioned).; 24142417; 25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous; PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previoulsy reported cases. The Authors state Screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance; 18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L); 25737287 to 24142417; 25737287 26990861; 18420150.; 25914261; 25737287; 18243799; 26990861; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 18420150; 22842711; 25142429 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.81 | APP | Louise Daugherty Publications for gene APP were changed from 22503161; 23028126 to 2111584; 23028126; 22503161 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.80 | PRKRA |
Louise Daugherty changed review comment from: 18420150 - a novel heterozygous variant c.266_267delAT;25914261;26990861;22842711;24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation;25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism;22842711 describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa;18243799;25142429;http://www.ncbi.nlm.nih.gov/books/NBK1155/;18420150;p.H89fsX20 was reported in a proband with early childhood-onset leg dystonia (though testing in the parents was not mentioned).;24142417;25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous;PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previoulsy reported cases. The Authors state Screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance;18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L);25737287; to: 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 Edit your comment Delete comment 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. |
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| Neurodegenerative disorders, adult onset v1.80 | PRKRA | Louise Daugherty commented on gene: PRKRA: 18420150 - a novel heterozygous variant c.266_267delAT;25914261;26990861;22842711;24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation;25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism;22842711 describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa;18243799;25142429;http://www.ncbi.nlm.nih.gov/books/NBK1155/;18420150;p.H89fsX20 was reported in a proband with early childhood-onset leg dystonia (though testing in the parents was not mentioned).;24142417;25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous;PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previoulsy reported cases. The Authors state Screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance;18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L);25737287 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.78 | CHMP2B | Louise Daugherty commented on gene: CHMP2B: Comment: - PMID: 20352044 conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.78 | CHMP2B | Louise Daugherty changed review comment from: 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. Comment: - We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.78 | CHMP2B | Louise Daugherty changed review comment from: 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.; to: 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. Comment: - We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.78 | CHMP2B | Louise Daugherty Publications for gene: CHMP2B were set to PMID: 20352044 - We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.74 | APP | Louise Daugherty commented on gene: APP: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.72 | OPHN1 | Nick Beauchamp reviewed gene: OPHN1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.72 | APP | Nick Beauchamp reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: ; Publications: 2111584; Phenotypes: Clinical syndrome Alzheimer disease, Dementia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.67 | APP | Louise Daugherty Source Yorkshire and North East GLH was added to APP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.45 | KIAA1161 | Louise Daugherty commented on gene: KIAA1161: added new-gene-name tag, new approved HGNC gene symbol for KIAA1161 is MYORG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.11 | APP | Louise Daugherty reviewed gene: APP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.10 | APP | James Polke reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.9 | APP | Louise Daugherty Source NHS GMS was added to APP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v1.8 | APP | Louise Daugherty Source London North GLH was added to APP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v0.125 | OPHN1 | Louise Daugherty Phenotypes for gene: OPHN1 were changed from to Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v0.78 | AR_CAG |
Louise Daugherty STR: AR_CAG was added STR: AR_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: AR_CAG. Mode of inheritance for STR: AR_CAG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for STR: AR_CAG were set to Spinal and bulbar muscular atrophy or Kennedy diseases 313200 Added comment: Source PanelApp panels : Amyotrophic lateral sclerosis/motor neuron disease v1.26 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.76 | ATN1_CAG |
Louise Daugherty STR: ATN1_CAG was added STR: ATN1_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATN1_CAG. Mode of inheritance for STR: ATN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: ATN1_CAG were set to 20301664; 8136840; 20301664; 8136840; 8136826; 7614090 Phenotypes for STR: ATN1_CAG were set to Dentatorubro-pallidoluysian atrophy 125370 Review for STR: ATN1_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary ataxia v1.150, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.46, Brain channelopathy v1.48, Parkinson Disease and Complex Parkinsonism v1.64. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.74 | ATXN10_ATTCT |
Louise Daugherty STR: ATXN10_ATTCT was added STR: ATXN10_ATTCT was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATXN10_ATTCT. Mode of inheritance for STR: ATXN10_ATTCT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: ATXN10_ATTCT were set to Spinocerebellar ataxia 10 603516 Review for STR: ATXN10_ATTCT was set to GREEN Added comment: Source PanelApp panels :Hereditary spastic paraplegia v1.143, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.46, Hereditary ataxia v1.150 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.72 | ATXN1_CAG |
Louise Daugherty STR: ATXN1_CAG was added STR: ATXN1_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATXN1_CAG. Mode of inheritance for STR: ATXN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: ATXN1_CAG were set to Spinocerebellar ataxia 1 164400 Review for STR: ATXN1_CAG was set to GREEN Added comment: Source PanelApp panels :Hereditary ataxia v1.150, Hereditary spastic paraplegia v1.143, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.46, Parkinson Disease and Complex Parkinsonism v1.64. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.70 | ATXN2_CAG |
Louise Daugherty STR: ATXN2_CAG was added STR: ATXN2_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATXN2_CAG. Mode of inheritance for STR: ATXN2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: ATXN2_CAG were set to Spinocerebellar ataxia 2 183090 Review for STR: ATXN2_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary ataxia v1.150, Hereditary spastic paraplegia v1.143, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.46, Early onset dystonia v1.76, Parkinson Disease and Complex Parkinsonism v1.64. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.65 | ATXN3_CAG |
Louise Daugherty STR: ATXN3_CAG was added STR: ATXN3_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATXN3_CAG. Mode of inheritance for STR: ATXN3_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: ATXN3_CAG were set to Machado-Joseph disease 109150 Review for STR: ATXN3_CAG was set to GREEN Added comment: Source PanelApp panels : Early onset dystonia v1.76, Parkinson Disease and Complex Parkinsonism v1.64, Hereditary ataxia v1.150, Hereditary spastic paraplegia v1.143. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.63 | CSTB_CCCCGCCCCGCG |
Louise Daugherty STR: CSTB_CCCCGCCCCGCG was added STR: CSTB_CCCCGCCCCGCG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: CSTB_CCCCGCCCCGCG. Mode of inheritance for STR: CSTB_CCCCGCCCCGCG was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for STR: CSTB_CCCCGCCCCGCG were set to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 Review for STR: CSTB_CCCCGCCCCGCG was set to GREEN Added comment: Source PanelApp panels : Brain channelopathy v1.48, Hereditary ataxia v1.150. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.61 | FXN_GAA |
Louise Daugherty STR: FXN_GAA was added STR: FXN_GAA was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: FXN_GAA. Mode of inheritance for STR: FXN_GAA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for STR: FXN_GAA were set to Friedreich ataxia 229300 Review for STR: FXN_GAA was set to GREEN Added comment: Source PanelApp panels : Hereditary spastic paraplegia v1.143, Hereditary ataxia v1.150 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.59 | HTT_CAG |
Louise Daugherty STR: HTT_CAG was added STR: HTT_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: HTT_CAG. Mode of inheritance for STR: HTT_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: HTT_CAG were set to Huntington disease 143100 Review for STR: HTT_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary spastic paraplegia v1.143, Parkinson Disease and Complex Parkinsonism v1.64, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.46, Hereditary ataxia v1.150 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.57 | ATXN7_CAG |
Louise Daugherty STR: ATXN7_CAG was added STR: ATXN7_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: ATXN7_CAG. Mode of inheritance for STR: ATXN7_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: ATXN7_CAG were set to Spinocerebellar ataxia 7 164500 Review for STR: ATXN7_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary spastic paraplegia v1.141, Hereditary ataxia v1.148. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.55 | C9orf72_GGGGCC |
Louise Daugherty STR: C9orf72_GGGGCC was added STR: C9orf72_GGGGCC was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: C9orf72_GGGGCC. Mode of inheritance for STR: C9orf72_GGGGCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: C9orf72_GGGGCC were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 Review for STR: C9orf72_GGGGCC was set to GREEN Added comment: Source PanelApp panels : Parkinson Disease and Complex Parkinsonism v1.64, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.45, Amyotrophic lateral sclerosis/motor neuron disease v1.26 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.53 | CACNA1A_CAG |
Louise Daugherty STR: CACNA1A_CAG was added STR: CACNA1A_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: CACNA1A_CAG. Mode of inheritance for STR: CACNA1A_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: CACNA1A_CAG were set to Spinocerebellar ataxia 6 183086 Review for STR: CACNA1A_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary ataxia v1.148, Brain channelopathy v1.46, Hereditary spastic paraplegia v1.141. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.51 | JPH3_CTG |
Louise Daugherty STR: JPH3_CTG was added STR: JPH3_CTG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: JPH3_CTG. Mode of inheritance for STR: JPH3_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: JPH3_CTG were set to Huntington disease-like 2 606438 Review for STR: JPH3_CTG was set to GREEN Added comment: Source PanelApp panels : Parkinson Disease and Complex Parkinsonism v1.64, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.45, Early onset dystonia v1.76. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.49 | NOP56_GGCCTG |
Louise Daugherty STR: NOP56_GGCCTG was added STR: NOP56_GGCCTG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: NOP56_GGCCTG. Mode of inheritance for STR: NOP56_GGCCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for STR: NOP56_GGCCTG were set to Spinocerebellar ataxia 36 614153 Review for STR: NOP56_GGCCTG was set to GREEN Added comment: Source PanelApp panels : Hereditary ataxia v1.148, Amyotrophic lateral sclerosis/motor neuron disease v1.26, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.45. Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.38 | PPP2R2B_CAG |
Louise Daugherty STR: PPP2R2B_CAG was added STR: PPP2R2B_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: PPP2R2B_CAG. Mode of inheritance for STR: PPP2R2B_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: PPP2R2B_CAG were set to 20301381 Phenotypes for STR: PPP2R2B_CAG were set to Spinocerebellar ataxia 12 604326 Review for STR: PPP2R2B_CAG was set to GREEN Added comment: Source PanelApp panels : Parkinson Disease and Complex Parkinsonism v1.64, Hereditary spastic paraplegia v1.141, Hereditary ataxia v1.148 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.36 | TBP_CAG |
Louise Daugherty STR: TBP_CAG was added STR: TBP_CAG was added to Neurodegenerative disorders - adult onset. Sources: Expert list STR tags were added to STR: TBP_CAG. Mode of inheritance for STR: TBP_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: TBP_CAG were set to 20301611 Phenotypes for STR: TBP_CAG were set to Spinocerebellar ataxia 17 607136 Review for STR: TBP_CAG was set to GREEN Added comment: Source PanelApp panels : Hereditary ataxia v1.148, Parkinson Disease and Complex Parkinsonism v1.64, Hereditary spastic paraplegia v1.141, Brain channelopathy v1.46, Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.45 Sources: Expert list |
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| Neurodegenerative disorders, adult onset v0.2 | PRKRA |
Rebecca Foulger gene: PRKRA was added gene: PRKRA was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: PRKRA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRKRA were set to 18420150 - a novel heterozygous variant c.266_267delAT; 25914261; 26990861; 22842711; 24142417 - Compound heterozygous variants were reported in a patient with early onset dystonia c.665C>T (p.P222L) inherited from his mother, and c.637T>C (p.C213R) was a novel mutation; 25142429 In a Polish family, the homozygous p.Pro222Leu mutation segregated with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism; 22842711 describes the clinical features of three original cases with homozygous PRKRA variants - the patients presented with either a pure generalised dystonia or with a dystonia-parkinsonism that was relatively unresponsive to L-dopa; 18243799; 25142429; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 18420150; p.H89fsX20 was reported in a proband with early childhood-onset leg dystonia (though testing in the parents was not mentioned).; 24142417; 25737287 Compound het variants (c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe)) identified in the two affected siblings reported with dystonia without parkinsonism, unaffected family members were heterozygous; PMID: 26990861 - c.665C>T homozygous variant was identified in 3 affected siblings with Early-Onset Generalized Dystonia-Parkinsonism (and was heterozygous in the unaffected patients and an unaffected sibling). It was confirmed by Sanger sequencing and had a frequency of 0.01% in the Exome Aggregation Consortium database, predicted to be deleterious by 2 of 6 in silico tools. They showed it was within a founder haplotype shared by all previoulsy reported cases. The Authors state Screening of PRKRA is warranted in all patients with early-onset generalized dystonia, or dystonia parkinsonism compatible with autosomal recessive inheritance; 18243799 - two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. A region of homozygosity was found in all affected individuals, and narrowed down to the homozygous variant c.665C>T (P222L); 25737287 Phenotypes for gene: PRKRA were set to Dystonia 16; early-onset generalized dystonia-parkinsonism (DYT16), non-responsive to levo-dopa; Early-Onset Generalized Dystonia-Parkinsonism; Early Onset Complex Disease |
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| Neurodegenerative disorders, adult onset v0.2 | CHMP2B |
Rebecca Foulger gene: CHMP2B was added gene: CHMP2B was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: CHMP2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CHMP2B were set to PMID: 20352044 - We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype. Phenotypes for gene: CHMP2B were set to Dementia, familial, nonspecific, 600795Amyotrophic lateral sclerosis 17, 614696; Frontotemporal Dementia |
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| Neurodegenerative disorders, adult onset v0.2 | APP |
Rebecca Foulger gene: APP was added gene: APP was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green Mode of inheritance for gene: APP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: APP were set to 22503161; 23028126 Phenotypes for gene: APP were set to Clinical syndrome Alzheimer disease; Dementia |
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