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Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Classified gene: ARPP21 as Amber List (moderate evidence)
Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two independent large-scale genetic studies (PMIDs: 38960585 & 41917433) linked ARRP21 to ALS with consistent variants (p.Pro529Leu/ p.Pro563Leu & p.Pro747Leu) and clinical severity, but no functional validation of any disease variant exists, analysis suggested variant embedded in founder-type haplotype and replication failed in Asian/Australian cohorts. ClinGen GCEP has still rated it with 'Limited' evidence, with it's last review on 14 January 2025. Hence, this gene should be rated amber with this evidence.

The 'watchlist' tag has been added to re-review once functional data or a formal GCEP upgrade emerge.
Neurodegenerative disorders, adult onset v9.11 ARPP21 Achchuthan Shanmugasundram Gene: arpp21 has been classified as Amber List (Moderate Evidence).
Neurodegenerative disorders, adult onset v9.10 ARPP21 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: ARPP21.
Neurodegenerative disorders, adult onset v9.10 ARPP21 Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 8120638; 29581509; 30811981; 31653410; 3358193; 38960585; 41917433
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
Neurodegenerative disorders, adult onset v9.9 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 33581934, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.9 ARPP21 Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433
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
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 3358193, 38960585, 41917433
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
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 3358193, 38960585, 41917433
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.
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.

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
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 38960585, 41917433
Neurodegenerative disorders, adult onset v9.8 ARPP21 Achchuthan Shanmugasundram gene: ARPP21 was added
gene: ARPP21 was added to Neurodegenerative disorders, adult onset. Sources: Literature
Mode of inheritance for gene: ARPP21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433
Phenotypes for gene: ARPP21 were set to amyotrophic lateral sclerosis, MONDO:0004976
Review for gene: ARPP21 was set to AMBER
Added comment: 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.
Sources: Literature
Neurodegenerative disorders, adult onset v9.7 GLT8D1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber despite having large number of cases and some functional data (zebrafish motor deficits, neuronal cell morphology changes, enzyme activity loss). This is because several reported variants were excluded from scoring due to population frequencies too high to be consistent with disease, gene-wide burden analysis shows no significant ALS association once the exon 4 cluster is excluded, and several cases with p.Arg92Cys variant also co-carrying ARPP21 variant. In addition, this gene is rated as 'Limited' in ClinGen for ALS phenotype.
Neurodegenerative disorders, adult onset v9.5 GLT8D1 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 (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 confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).; 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 (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 confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

Burden analysis showed there is no significant ALS-association within GLT8D1 when exon 4 is excluded. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

Burden analysis in sALS cohort showed that there is no significant enrichment of rare GLT8D1 variants versus gnomAD East Asian controls at either whole-gene level (4 variants/1,410 combined sALS cases vs 25 variants/9,766 gnomAD controls) or exon 4–specific level (0 variants in sALS vs 3 in controls).

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).
Neurodegenerative disorders, adult onset v9.5 GLT8D1 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 (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 confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.; 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 (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 confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).