Description
Brain channelopathy eligibility statement:

Brain channelopathy inclusion criteria (29579)
- Episodic disorder that often causes a combination of ataxia with walking problems, abnormal extra movements, stiff legs, weakness, headache and nausea.  
- Episodes lasting a few minutes or hours.  
- There may be a dystonic component and some patients are exhausted for many hours afterwards.  
- Attacks are not always the same, even with the same genetic defect. 
- Arms can be affected like legs 
- Migraine type headaches are frequently associated as is dysarthria 
- Some patients have a primary headache in the form of hemiplegic migraine (FHM), cluster headache, SUNCT or SUNA 
- MRI brain and cord to exclude common causes such as tumours, discs, demyelinating causes 
- Family history of often present in AD or AR forms, X linked pattern rare 
- Often drugs such as Lamotrigine or acetazolamide are effective  

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.

Brain channelopathy exclusion criteria (29579)

Prior genetic testing guidance (29579)
- 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.

Brain channelopathy prior genetic testing genes (29579)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: 
 - KCNA1, PRRT2 as appropriate 
- CACNA1A (only in dominant, long duration episodic ataxia)

Closing statement (29579)
These requirements will be kept under continual review during the main programme and may be subject to change.

3 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

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

    Group: Other
    Workplace: Other

  • Arianna Tucci (Genomics England Curator)

    Group: Other
    Workplace: Other

26 Entities

25 reviewed, 18 green

List Entity Reviews Mode of inheritance Details
26 Entitiess
Green Green List (high evidence)
Xp11.23 region (includes MAOA and MAOB) Loss
ISCA-37468-Loss
Region
0 reviews
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than females)
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • episodes of sudden loss of muscle tone
  • severe intellectual disability
  • exiting behavior
  • short stature
  • eleveated serotonin levels
  • autistic features
  • lip-smacking
  • hypotonia
  • stereotypical hand movements
Tags
Green Green List (high evidence)
ADCY5
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Familial dyskinesia 606703
Tags
Green Green List (high evidence)
ATP1A2
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • familial hemiplegic migraine type 2, 602481
  • familial basilar migraine 602481
  • alternating hemiplegia of childhood 104290
Tags
  • treatable
Green Green List (high evidence)
ATP1A3
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • DYSTONIA 12, 128235
  • ALTERNATING HEMIPLEGIA OF CHILDHOOD 2, 614820
Tags
  • treatable
Green Green List (high evidence)
ATP7B
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Wilson disease 277900
Tags
  • treatable
Green Green List (high evidence)
CACNA1A
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • UKGTN
Phenotypes
  • episodic ataxia type 2 (EA2),108500
  • familial hemiplegic migraine type 1, 141500
Tags
  • treatable
Green Green List (high evidence)
CACNB4
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • EPISODIC ATAXIA, TYPE 5
  • EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 9
Tags
  • treatable
Green Green List (high evidence)
GLRA1
1 review
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • 149400 HYPEREKPLEXIA, HEREDITARY 1
Tags
Green Green List (high evidence)
GLRB
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • 614619 HYPEREKPLEXIA 2
Tags
Green Green List (high evidence)
KCNA1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • UKGTN
Phenotypes
  • EPISODIC ATAXIA, TYPE 1
  • myokymia with periodic ataxia
Tags
  • treatable
Green Green List (high evidence)
KCNQ2
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Myokymia, 121200
Tags
Green Green List (high evidence)
KCNQ3
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Seizures, benign neonatal, type 2, 121201
Tags
Green Green List (high evidence)
PNKD
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • PAROXYSMAL NONKINESIGENIC DYSKINESIA 1
Tags
Green Green List (high evidence)
PRRT2
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • UKGTN
Phenotypes
  • CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS
  • EPISODIC KINESIGENIC DYSKINESIA 1
  • SEIZURES, BENIGN FAMILIAL INFANTILE, 2
  • episodic kinesigenic dyskinesia
  • dystonia and occasionally hemiplegic migraine and epilepsy
Tags
  • treatable
Green Green List (high evidence)
SCN1A
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • familial hemiplegic migraine 3
  • Dravet syndrome
  • several epilepsy, convulsion and migraine disorders.
Tags
Green Green List (high evidence)
SCN8A
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • epilepsy
  • paroxysmal kinesigenic dyskinesias
Tags
Green Green List (high evidence)
SLC1A3
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • EPISODIC ATAXIA, TYPE 6
Tags
Green Green List (high evidence)
SLC2A1
3 reviews
1 green
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • paroxysmal exertion-induced dyskinesia with or without epilepsy and/or hemolytic anemia
  • EPILEPSY, IDIOPATHIC GENERALIZED
  • GLUT1 DEFICIENCY SYNDROME 1
  • dystonia 9
Tags
  • treatable
Green Green List (high evidence)
SLC6A5
1 review
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • 614618 HYPEREKPLEXIA 3
Tags
Amber Amber List (moderate evidence)
KCNK18
3 reviews
1 red
Not set
Sources
  • Expert Review Amber
  • UKGTN
Phenotypes
  • MIGRAINE, WITH OR WITHOUT AURA, SUSCEPTIBILITY TO, 13
Tags
Red Red List (low evidence)
ATN1
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Other
Phenotypes
  • Dentatorubro-pallidoluysian atrophy 125370
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Red Red List (low evidence)
ATN1_CAG
STR
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
Phenotypes
  • Dentatorubro-pallidoluysian atrophy 125370
Tags
  • STR
Red Red List (low evidence)
HTT
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Huntington disease 143100
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Red Red List (low evidence)
HTT_CAG
STR
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
Phenotypes
  • Huntington disease 143100
Tags
  • STR
Red Red List (low evidence)
NKX2-1
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Chorea, hereditary benign 118700
  • Choreoathetosis, hypothyroidism, and neonatal respiratory distress 610978
Tags
Red Red List (low evidence)
SCN9A
2 reviews
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Erythermalgia, primary, 133020
  • Insensitivity to pain, channelopathy-associated, 243000
  • Paroxysmal extreme pain disorder, 167400
  • Febrile seizures, familial, 3B, 613863
  • Epilepsy, generalized, with febrile seizures plus, type 7, 613863
  • Congenital Indifference to Pain
  • Dysosteosclerosis
  • Erythermalgia, Primary
  • Paroxysmal Extreme Pain Disorder
  • Hereditary Sensory Neuropathy
Tags

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