Description
Amyotrophic lateral sclerosis or motor neuron disease inclusion criteria (29537)
- Progressive upper and/or lower motor neuron disease degeneration with clinical features of amyotrophy, spasticity, bulbar/pseudo-bulbar involvement  
- EMG/NCS consistent with MND 
- Positive family history of other affected family members with ALS or with FTD/ALS like phenotype or disease onset below 40 years.  

Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease.  In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.

Amyotrophic lateral sclerosis or motor neuron disease exclusion criteria (29537)
- Identified underlying cause for clinical syndrome e.g. multi-focal motor neuropathy, lymphoma

Prior genetic testing guidance (29537)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Amyotrophic lateral sclerosis or motor neuron disease prior genetic testing genes (29537)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: 
 - C9ORF72, SOD1

Closing statement (29537)
These requirements will be kept under continual review during the main programme and may be subject to change.

8 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Nayana Lahiri (South London GMC)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS diagnostic lab

  • Arianna Tucci (Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square)

    Group: Other
    Workplace: Other

  • Caroline Wright (Genomics England Curator)

    Group: Other
    Workplace: Genomics England

  • Andrew Douglas (University of Southampton / Wessex Clinical Genetics Service)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Alice Gardham (Genomics England)

    Group: Other
    Workplace: Other

  • Arianna Tucci (Genomics England Curator)

    Group: Other
    Workplace: Other

30 genes

30 reviewed, 19 green

List Gene Reviews Mode of inheritance Details
30 genes
Green Green List (high evidence)
ALS2
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis, Recessive
  • Amyotrophic lateral sclerosis 2, juvenile, 205100
  • Primary lateral sclerosis, juvenile, 606353
  • Spastic paralysis, infantile onset ascending, 607225
Green Green List (high evidence)
ANG
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Illumina TruGenome Clinical Sequencing Services
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Amyotrophic lateral sclerosis 9, 611895
  • familial amyotrophic lateral sclerosis (ALS9)
Green Green List (high evidence)
AR
1 review
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Expert Review
Phenotypes
  • Spinal and bulbar muscular atrophy of Kennedy, 313200
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Green Green List (high evidence)
DCTN1
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Neuropathy, distal hereditary motor, type VIIB, 607641
  • {Amyotrophic lateral sclerosis, susceptibility to}, 105400
  • Perry syndrome, 168605
Green Green List (high evidence)
FIG4
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Charcot-Marie-Tooth disease, type 4J, 611228
Green Green List (high evidence)
FUS
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Expert
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Amyotrophic lateral sclerosis 6, autosomal recessive, with or without frontotemporal
  • Amyotrophic Lateral Sclerosis, Dominant
Green Green List (high evidence)
HNRNPA1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • ?Inclusion body myopathy wtih early-onset Paget disease without frontotemporal
Green Green List (high evidence)
OPTN
1 review
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis, Recessive
  • Glaucoma 1, open angle, E, 137760
Green Green List (high evidence)
PFN1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Amyotrophic lateral sclerosis 18, 614808
Green Green List (high evidence)
SETX
4 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
  • Emory Genetics Laboratory
  • Expert Review Green
Phenotypes
  • Amyotrophic lateral sclerosis 4, juvenile 602433
Green Green List (high evidence)
SIGMAR1
2 reviews
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Amyotrophic lateral sclerosis 16, juvenile, 614373
Green Green List (high evidence)
SLC52A2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Brown-Vialetto-Van Laere syndrome 2
Tags
  • treatable
Green Green List (high evidence)
SLC52A3
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Brown-Vialetto-Van Laere syndrome 1
  • Fazio-Londe disease
Green Green List (high evidence)
SOD1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Expert
  • Expert Review Green
  • Eligibility statement prior genetic testing
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Amyotrophic lateral sclerosis 1, 105400
  • amyotrophic lateral sclerosis
Green Green List (high evidence)
TARDBP
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
  • Expert Review Green
  • Expert
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Amyotrophic lateral sclerosis 10, with or without FTD, 612069
Tags
  • polygenic
Green Green List (high evidence)
TBK1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Literature
  • Expert Review Green
Phenotypes
  • Amyotrophic lateral sclerosis
  • fronto-temporal dementia
Green Green List (high evidence)
UBQLN2
2 reviews
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia, 300857
Green Green List (high evidence)
VAPB
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis, Dominant
  • Amyotrophic lateral sclerosis 8, 608627
Green Green List (high evidence)
VCP
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
  • Radboud University Medical Center, Nijmegen
  • Expert Review Green
Phenotypes
  • Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954
  • Amyotrophic Lateral Sclerosis, Dominant
  • familial amyotrophic lateral sclerosis (ALS14)
Amber Amber List (moderate evidence)
NEFH
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert list
  • Expert Review Amber
Phenotypes
  • susceptibility to amyotrophic lateral sclerosis (ALS)
Red Red List (low evidence)
ATXN2
1 review
Not set
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinocerebellar ataxia 2, 183090
  • {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183090
Tags
  • nucleotide-repeat-expansion
Red Red List (low evidence)
C9orf72
3 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Eligibility statement prior genetic testing
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
  • Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3
  • Hexanucleotide repeat expansion
  • Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Tags
  • nucleotide-repeat-expansion
Red Red List (low evidence)
CHCHD10
1 review
Not set
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • ?Myopathy, isolated mitochondrial, autosomal dominant, 616209
Red Red List (low evidence)
CHMP2B
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Dementia, familial, nonspecific, 600795
  • Amyotrophic lateral sclerosis 17, 614696
Red Red List (low evidence)
ERBB4
3 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Amyotrophic lateral sclerosis 19, 615515
Red Red List (low evidence)
GRN
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Expert
Red Red List (low evidence)
HFE
1 review
Unknown
Sources
  • Literature
Red Red List (low evidence)
SLC52A1
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Expert list
Phenotypes
  • Riboflavin deficiency (condition resembling childhood-onset motor neurone disease)
Red Red List (low evidence)
UNC13A
1 review
Unknown
Sources
  • Literature
Red Red List (low evidence)
VEGFA
1 review
Unknown
Sources
  • Literature

3 STRs

3 reviewed, 2 green

List STR Reviews Mode of inheritance Details
3 STRss
Green Green List (high evidence)
C9orf72_GGGGCC
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Green
Phenotypes
  • Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Tags
  • STR
Green Green List (high evidence)
AR_CAG
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert list
  • Expert Review Green
Phenotypes
  • Spinal and bulbar muscular atrophy or Kennedy diseases 313200
Tags
  • STR
Red Red List (low evidence)
ATXN2_CAG
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
Phenotypes
  • Spinocerebellar ataxia 2 183090
Tags
  • STR

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