Description
Eligibility statement for Familial cerebral small vessel disease:

Familial cerebral small vessel disease inclusion criteria (36473)
•	Clinical features consistent with cerebral small vessel disease: either lacunar stroke or vascular cognitive impairment/dementia, AND
•	MRI confirmed evidence of cerebral small vessel disease as evidenced by; multiple lacunar infarcts and/or confluent white matter hyperintensities, AND
•	Early onset cerebral SVD (<60 years) without cardiovascular risk factors or affected first degree family member

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.

Familial cerebral small vessel disease exclusion criteria (36473)
•	Causes of white matter disease other than cerebral small vessel disease (e.g. multiple sclerosis, vasculitis, leukodystrophy).
•	Cases with NOTCH3 mutations

Prior genetic testing guidance (36473)
- 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.

Familial cerebral small vessel disease prior genetic testing genes (36473)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:
NOTCH3

Closing statement (36473)
These requirements will be kept under continual review during the main programme and may be subject to change.

4 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Caroline Wright (Genomics England Curator)

    Group: Other
    Workplace: Genomics England

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Rhea Tan (University of Cambridge)

    Group: GeCIP domain
    Workplace: Research lab

15 Entities

15 reviewed, 12 green

List Entity Reviews Mode of inheritance Details
15 Entitiess
Green Green List (high evidence)
ABCC6
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
  • Literature
Phenotypes
  • Pseudoxanthoma elasticum 264800 AR
  • Pseudoxanthoma elasticum, forme fruste 177850 AD
Tags
Green Green List (high evidence)
APP
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Haemorrhagic stroke
  • stroke
  • ischaemic stroke
  • leukoencephalopathy
  • seizures
  • Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants 605714
Tags
Green Green List (high evidence)
ATP1A2
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebral small vessel disease
  • coma
  • encephalopathy
  • Migraine, familial basilar 602481
  • Migraine, familial hemiplegic, 2 602481
Tags
Green Green List (high evidence)
CACNA1A
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Episodic ataxia, type 2 108500
  • Migraine, familial hemiplegic, 1 141500 AD
  • Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500
  • Spinocerebellar ataxia 6 183086
Tags
Green Green List (high evidence)
COL3A1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • stroke
  • ischemic stroke
  • haemorrhagic stroke
  • dissection
  • vertebral artery dissection
  • Ehlers-Danlos syndrome, type IV 130050
Tags
Green Green List (high evidence)
COL4A1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebral Small Vessel Disease
  • stroke
  • migraine
  • Axenfeld-Rieger Anomaly
  • cognitive impairment
  • dementia
  • seizures
  • myopathy
  • infantile hemiparesis
  • developmental delay
  • Porencephaly 1 175780
  • {Hemorrhage, intracerebral, susceptibility to} 614519
Tags
Green Green List (high evidence)
COL4A2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • porencephaly
  • infantile heiparesis, intracerebral haemorrhages
  • Porencephaly 2 614483
  • {Hemorrhage, intracerebral, susceptibility to} 614519
Tags
Green Green List (high evidence)
FOXC1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Expert list
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Stroke
  • Dandy Walker Syndrome
  • Hearing Impairment
  • Axenfeld-Rieger syndrome, type 3, Rieger or Axenfeld anomalies 602482
  • Iridogoniodysgenesis, type 1, Iris hypoplasia and glaucoma 601631
Tags
Green Green List (high evidence)
GLA
2 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
  • Emory Genetics Laboratory
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebral Small Vessel Disease
  • Stroke
  • Ischemic Stroke
  • haemorrhagic stroke
  • Fabry disease, Fabry disease, cardiac variant 301500
Tags
Green Green List (high evidence)
HTRA1
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebral small vessel disease
  • strokes, dementia
  • cognitive impairment
  • psychiatric disturbance
  • alopecia
  • degenerative disc disease
  • CARASIL syndrome 600142 AR
  • Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 616779
Tags
Green Green List (high evidence)
NOTCH3
4 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Other
  • UKGTN
Phenotypes
  • Migraine
  • Encephalopathy
  • Stroke
  • Cognitive impairment
  • Dementia
  • Seizures
  • Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310
Tags
Green Green List (high evidence)
TREX1
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • retinal vasculopathy with cerebral leukodystrophy
  • cerebroretinal vasculopathy
  • hereditary endotheliopathy, retinopathy, nephropathy and stroke
  • stroke, hereditary vascular retinopathy
  • retinopathy
  • nephropathy
  • Aicardi-Goutieres syndrome 1, dominant and recessive 225750 AR, AD
  • Vasculopathy, retinal, with cerebral leukodystrophy 192315 AD
Tags
Red Red List (low evidence)
CST3
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Expert list
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Stroke
  • haemorrhagic stroke
  • dementia
  • Cerebral amyloid angiopathy 105150
Tags
  • founder-effect
  • watchlist
Red Red List (low evidence)
ITM2B
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Expert list
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • ischaemic stroke
  • haemorrhagic stroke
  • stroke
  • spastic tetraparesis
  • tetraparesis
  • ementia, familial British 176500
  • Dementia, familial Danish 117300
Tags
Red Red List (low evidence)
SCN1A
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Cerebral small vessel disease
  • Dravet syndrome 607208
  • Epilepsy, generalized, with febrile seizures plus, type 2 604403
  • Febrile seizures, familial, 3A 604403
  • Migraine, familial hemiplegic, 3 609634
Tags

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