Description
NB. Clinical test guidance:
Imaging diagnostics refers to Brain MRI

Kleine-Levin syndrome and other inherited sleep disorders inclusion criteria (29583)
-Recurrent hypersomnia: 
-Recurrent episodes of excessive daytime sleepiness lasting for 2 days-4 weeks 
-Episodes recur at least once per year -Alertness, cognitive function and behavior are normal between episodes 
-Hypersomnia 
-AND at least 1 of the following: 
-Cognitive abnormalities 
– ex confusion, derealisation(“déjà vu” during episodes, dream-like state or experiencing out of body hallucinations 
-Abnormal behaviour – irritability, aggression 
-Hyperphagia 
OR 
-Recurrent daytime hypersomnia: 
-Sudden onset of sleep or "sleep attacks" 
-Other symptoms can include cataplexy, hypnagogic hallucinations and Sleep paralysis 
-A positive family history 
OR 
-Involuntary kicking and jerking movements of the legs and arms often repeated 100s of times during the night 
-Unaware of their multiple night-time awakenings unless they are witnessed by a bed partner 
-In extreme cases these brief arousals following the leg movements disturb sleep so much that they cause excessive daytime sleepiness 
-A +ve family history 
OR 
-The symptoms of parasomnias: 
-Sleepwalking—takes place during deep sleep, not REM sleep when dreams typically occur 
-Night terrors—these severe attacks cause people, usually children, to appear to wake up and scream in fear or panic 
-Sleep-eating disorders—these episodes occur during partial awakenings from deep sleep and cause individuals to eat without any knowledge of what they are doing. 
-A +ve family history 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.

Kleine-Levin syndrome and other inherited sleep disorders exclusion criteria (29583)
- No structural or inflammatory (MS-like) lesions on brain MRI.
- No atypical depression
- No sleep disorders (exclude Narcolepsy and Menstruation-related hypersomnia)
- No substance abuse (particularly benzodiazepine)
- No temporal lobe epilepsy
- Metabolic Encephalopathy
- Lyme disease
- Acute intermittent porphyria

Prior genetic testing guidance (29583)
- 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.

Closing statement (29583)
These requirements will be kept under continual review during the main programme and may be subject to change.

3 reviewers

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Rosa Peraita-Adrados (Sleep and Epilepsy Unit-Clinical Neurophysiology Service. Gregorio Maranon University Hospital. Complutense University of Madrid (UCM).Madrid.Spain.)

    Group: Other NHS organisation
    Workplace: NHS clinical service

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

12 Entities

12 reviewed, 1 green

List Entity Reviews Mode of inheritance Details
12 Entitiess
Green Green List (high evidence)
DNMT1
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Neuropathy, hereditary sensory, type IE, 614116
  • Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, 604121
  • CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT
  • ADCADN
Tags
Amber Amber List (moderate evidence)
CSNK1D
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Advanced sleep-phase syndrome, familial, 2, 615224
Tags
Amber Amber List (moderate evidence)
MOG
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Narcolepsy 7, 614250
Tags
Red Red List (low evidence)
AKR1C2
1 review
Unknown
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Obesity, hyperphagia, and developmental delay
Tags
Red Red List (low evidence)
EIF3G
1 review
1 red
Unknown
Sources
  • Literature
Phenotypes
  • Narcolepsy
Tags
Red Red List (low evidence)
EXT1
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Familial case of narcolepsy with cataplexy NT1 associated with multiple exostoses (one family)
Tags
Red Red List (low evidence)
HCRT
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
Phenotypes
  • ?Narcolepsy 1, 161400
Tags
Red Red List (low evidence)
HLA-DQB1
1 review
Unknown
Sources
  • Other
Phenotypes
  • Kleine-Levin hibernation syndrome 148840
  • narcolepsy
Tags
Red Red List (low evidence)
NTRK2
1 review
Unknown
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
Phenotypes
  • Obesity, hyperphagia, and developmental delay, 613886
Tags
Red Red List (low evidence)
PER2
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Advanced sleep phase syndrome, familial, 1, 604348
Tags
Red Red List (low evidence)
SLC6A4
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • SLC6A4-Related Behavior Disorders
  • {Anxiety-related personality traits} 607834
  • {Obsessive-compulsive disorder} 164230
Tags
Red Red List (low evidence)
TRPV4
3 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Monozygotic twins concordant for Kleine-Levin Syndrome
  • recurrent hypersomnia
  • behavioral disturbances
  • compulsive eating and drinking (or decreased eating)
  • sexual disinhibition
  • irritability
  • confusion
  • feeling of unreality
  • altered tactile, gustative, and olphatory perceptions
  • apathi
  • impaired speech
  • impaired memory
  • depression and anxiety
  • transient symptoms at the end, amnesia, moderate elation and insomnia
  • normality between episodes
Tags

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