Brain channelopathy (Version 1.80)

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.

Panel Activity

9 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
Sarah Leigh (Genomics England Curator)

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
Zornitza Stark (Australian Genomics)

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

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

Group: Other
Workplace: Other

32 Entities

32 reviewed, 26 green

List	Entity	Reviews	Mode of inheritance	Details
Filter Entities 32 Entitiess
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)	ATN1_CAG STR	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Green NHS GMS Phenotypes Dentatorubral-pallidoluysian atrophy, OMIM:125370 Tags STR
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	4 reviews 1 green 1 red	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Eligibility statement prior genetic testing Expert Review Green UKGTN Phenotypes Episodic ataxia, type 2, OMIM:108500 Migraine, familial hemiplegic, 1, OMIM:141500 Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 Tags treatable
Green Green List (high evidence)	CACNA1A_CAG STR	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert Review Expert Review Green NHS GMS Phenotypes Spinocerebellar ataxia 6, OMIM:183086 Tags STR
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)	CSTB_CCCCGCCCCGCG STR	2 reviews	BIALLELIC, autosomal or pseudoautosomal	Sources Expert Review Expert Review Green NHS GMS Phenotypes Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800 Tags STR
Green Green List (high evidence)	GLRA1	1 review 1 green	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Expert Review Expert Review Green Phenotypes Hyperekplexia, hereditary 1, 149400 Tags
Green Green List (high evidence)	GLRB	1 review 1 green	BIALLELIC, autosomal or pseudoautosomal	Sources Expert Review Expert Review Green Phenotypes Hyperekplexia 2, 614619 Tags
Green Green List (high evidence)	Xp11.23 region (includes MAOA and MAOB) Loss ISCA-37468-Loss Region	1 review	X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)	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)	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)	KCNJ2	2 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Green Phenotypes Andersen syndrome, OMIM:170390 Andersen-Tawil syndrome, MONDO:0008222 Episodic weakness Periodic paralysis Tags
Green Green List (high evidence)	KCNMA1	3 reviews 1 green	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Expert list Expert Review Green Phenotypes Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446 Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276 Tags
Green Green List (high evidence)	KCNQ2	1 review 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Green Phenotypes Myokymia, 121200 Tags
Green Green List (high evidence)	KCNQ3	1 review 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Green 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 Seizures, benign familial infantile, 5, OMIM:617080 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 Hyperekplexia 3, 614618 Tags
Green Green List (high evidence)	SPR	1 review 1 green	BOTH monoallelic and biallelic, autosomal or pseudoautosomal	Sources Expert Review Green Literature Phenotypes Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716 Tags
Green Green List (high evidence)	TBP_CAG STR	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert Review Expert Review Green NHS GMS Phenotypes Spinocerebellar ataxia 17, OMIM:607136 Tags STR
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	2 reviews 1 red	Other	Sources Expert Review Red Other Phenotypes Dentatorubral-pallidoluysian atrophy, OMIM:125370 Tags currently-ngs-unreportable nucleotide-repeat-expansion
Red Red List (low evidence)	HTT	2 reviews 1 red	Other	Sources Expert Review Expert Review Red Phenotypes Huntington disease, OMIM:143100 Tags currently-ngs-unreportable nucleotide-repeat-expansion
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
No list No list	HTT_CAG STR	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert list Expert Review Removed NHS GMS Phenotypes Huntington disease, OMIM:143100 Tags curated_removed STR

Brain channelopathy (Version 1.80)

9 reviewers

32 Entities

32 reviewed, 26 green

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