Amyotrophic lateral sclerosis/motor neuron disease (Version 1.69)

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.

Panel Activity

14 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
Louise Daugherty (Genomics England Curator)

Group: Other
Workplace: Other
Arianna Tucci (Genomics England Curator)

Group: Other
Workplace: Other
Eleanor Williams (Genomics England Curator)

Group: Other
Workplace: Other
Ivone Leong (Genomics England Curator)

Group: Other
Workplace: Other
Andrey Gagunashvili (UCL Great Ormond Street Institute of Child Health)

Group: GeCIP domain
Workplace: Other
Arina Puzriakova (Genomics England Curator)

Group: Other
Workplace: Other
Agnese Zarina (Rīga Stradiņš Univeristy)

Group: Other
Workplace: Other diagnostic lab

42 Entities

42 reviewed, 24 green

List	Entity	Reviews	Mode of inheritance	Details
Filter Entities 42 Entitiess
Green Green List (high evidence)	ALS2	1 review	BIALLELIC, autosomal or pseudoautosomal	Sources Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic lateral sclerosis 2, juvenile, OMIM:205100 Primary lateral sclerosis, juvenile, OMIM:606353 Tags
Green Green List (high evidence)	ANG	1 review	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic Lateral Sclerosis, Dominant Amyotrophic lateral sclerosis 9, 611895 familial amyotrophic lateral sclerosis (ALS9) Tags
Green Green List (high evidence)	AR_CAG STR	3 reviews 1 green	X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)	Sources Expert list Expert Review Green NHS GMS Phenotypes Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 Tags STR
Green Green List (high evidence)	C9orf72_GGGGCC STR	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Green NHS GMS Phenotypes Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550 Tags STR
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 Tags
Green Green List (high evidence)	FIG4	2 reviews	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic lateral sclerosis 11 OMIM:612577 amyotrophic lateral sclerosis type 11 MONDO:0012945 Charcot-Marie-Tooth disease, type 4J, OMIM:611228 Charcot-Marie-Tooth disease type 4J MONDO:0012640 Yunis Varon syndrome OMIM:216340 Yunis-Varon syndrome MONDO:0008995 Tags
Green Green List (high evidence)	FUS	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen UKGTN Phenotypes Amyotrophic lateral sclerosis 6, autosomal recessive, with or without frontotemporal Amyotrophic Lateral Sclerosis, Dominant Tags
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 Tags
Green Green List (high evidence)	KIF5A	2 reviews 2 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Green Literature Phenotypes {Amyotrophic lateral sclerosis, susceptibility to, 25}, OMIM:617921 amyotrophic lateral sclerosis, susceptibility to, 25, MONDO:0060670 Tags
Green Green List (high evidence)	NEK1	2 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources ClinGen Expert Review Green Literature Research Phenotypes Amyotrophic lateral sclerosis, susceptibility to, 24, OMIM:617892 amyotrophic lateral sclerosis, susceptibility to, 24, MONDO:0054750 Tags
Green Green List (high evidence)	NOP56_GGCCTG STR	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert Review Expert Review Green NHS GMS Phenotypes Spinocerebellar ataxia 36, OMIM:614153 Tags STR
Green Green List (high evidence)	OPTN	2 reviews	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia, OMIM:613435 Tags
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 Tags
Green Green List (high evidence)	SETX	4 reviews 1 green	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Emory Genetics Laboratory Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433 Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, OMIM:606002 Tags
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 Tags
Green Green List (high evidence)	SLC52A2	2 reviews 1 green	BIALLELIC, autosomal or pseudoautosomal	Sources Expert list Expert Review Green Phenotypes Brown-Vialetto-Van Laere syndrome 2 Tags treatable
Green Green List (high evidence)	SLC52A3	3 reviews 1 green	BIALLELIC, autosomal or pseudoautosomal	Sources Expert list Expert Review Green Phenotypes Brown-Vialetto-Van Laere syndrome 1 Fazio-Londe disease Tags
Green Green List (high evidence)	SOD1	3 reviews 1 green	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Eligibility statement prior genetic testing Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic lateral sclerosis 1, OMIM:105400 Tags
Green Green List (high evidence)	SPAST	2 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Green Literature Research Phenotypes Spastic paraplegia 4, autosomal dominant, OMIM:182601 hereditary spastic paraplegia 4, MONDO:0008438 Tags
Green Green List (high evidence)	TARDBP	3 reviews 2 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen UKGTN 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 Expert Review Green Literature Phenotypes Amyotrophic lateral sclerosis fronto-temporal dementia Tags
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 Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic Lateral Sclerosis, Dominant Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia, 300857 Tags
Green Green List (high evidence)	VAPB	1 review	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Amyotrophic Lateral Sclerosis, Dominant Amyotrophic lateral sclerosis 8, 608627 Tags
Green Green List (high evidence)	VCP	1 review	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen UKGTN Phenotypes Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954 Amyotrophic Lateral Sclerosis, Dominant familial amyotrophic lateral sclerosis (ALS14) Tags
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) Tags
Red Red List (low evidence)	AR	2 reviews 1 green	Other	Sources Expert Review Expert Review Red Phenotypes Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 Tags currently-ngs-unreportable nucleotide-repeat-expansion
Red Red List (low evidence)	ATXN2	2 reviews	Other	Sources Expert Review Red Radboud University Medical Center, Nijmegen Phenotypes {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090 Tags currently-ngs-unreportable nucleotide-repeat-expansion
Red Red List (low evidence)	C9orf72	4 reviews 2 red	Other	Sources Eligibility statement prior genetic testing Expert Expert Review Red Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550 Tags currently-ngs-unreportable 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 Tags
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 Tags
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 Tags
Red Red List (low evidence)	GRN	1 review	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Expert Review Red Tags
Red Red List (low evidence)	HFE	1 review	Unknown	Sources Literature Tags
Red Red List (low evidence)	SLC52A1	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert list Expert Review Red Phenotypes Riboflavin deficiency (condition resembling childhood-onset motor neurone disease) Tags
Red Red List (low evidence)	UNC13A	1 review	Unknown	Sources Literature Tags
Red Red List (low evidence)	VEGFA	1 review	Unknown	Sources Literature Tags
No list No list	ANXA11	1 review	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Literature Phenotypes Amyotrophic lateral sclerosis 23 Tags
No list No list	ATXN2_CAG STR	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Removed NHS GMS Phenotypes {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090 Tags curated_removed STR
No list No list	MATR3	1 review	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Literature Phenotypes Amyotrophic lateral sclerosis 21 Tags
No list No list	SPG11	1 review	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Literature Phenotypes Amyotrophic lateral sclerosis 5, juvenile Tags
No list No list	SQSTM1	1 review	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Literature Phenotypes Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Tags
No list No list	TUBA4A	1 review	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Literature Phenotypes Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia Tags

Major version comments

Promoted to version 1 on 19th December 2016 following external review and internal curation

Amyotrophic lateral sclerosis/motor neuron disease (Version 1.69)

14 reviewers

42 Entities

42 reviewed, 24 green

1 review

Sources

Phenotypes

Tags

1 review

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

1 review

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

4 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

3 reviews

Sources

Phenotypes

Tags

2 reviews

Sources

Phenotypes

Tags