Rare Disease Conditions Eligibility Criteria v1.5.1

Transcription

1 Rare Disease Conditions Criteria v1.5.1 Document Record ID Key Work stream Rare Diseases Programme Director Mark Caulfield Status Final Document Owner Richard Scott Version Document Author Andrew Devereau, Richard Scott Ellen Thomas Version Date 21/7/2016

2 Quick links page Click on the section heading below to jump to the relevant section: Cardiovascular disorders ( ) Ciliopathies ( ) Dermatological disorders ( ) Dysmorphic and congenital abnormality syndromes ( ) Endocrine disorders ( ) Gastroenterological disorders ( ) Growth disorders ( ) Haematological disorders ( ) Hearing and ear disorders ( ) Metabolic disorders ( ) Neurology and neurodevelopmental disorders ( ) Ophthalmological disorders ( ) Renal and urinary tract disorders ( ) Respiratory disorders ( ) Rheumatological disorders ( ) Skeletal disorders ( ) Tumour syndromes ( ) Ultra-rare disorders ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

3 Document History The controlled copy of this document is maintained in the Genomics England internal document management system. Any copies of this document held outside of that system, in whatever format (for example, paper, attachment), are considered to have passed out of control and should be checked for currency and validity. This document is uncontrolled when printed. Version History Version Date Description /07/2016 First draft from completed v1.5 catalogue /07/2016 Minor changes following review /07/2016 Additional text added to introduction /07/2016 Revised to v1.5.1 in line with data model catalogue correcting errors /07/2016 Minor correction Reviewers This document must be reviewed by the following: Name Title Version Richard Scott Clinical Lead for Rare Disease 1.4 Approvers This document must be approved by the following: Name Responsibility Date Version Tom Fowler on behalf of Mark Caulfield Director of Public Health Chief Scientist 21/07/ RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

4 Contents Introduction Purpose of this document Structure and background to eligibility statements Changes since the last release Other changes to the rare diseases programme Rare Disease Conditions Criteria Cardiovascular disorders ( ) Arteriopathies ( ) Familial Hypercholesterolaemia ( ) Familial cerebral small vessel disease ( ) Connective Tissues Disorders and Aortopathies ( ) Familial Thoracic Aortic Aneurysm Disease ( ) Cardiac arrhythmia ( ) Brugada syndrome ( ) Long QT syndrome ( ) Catecholaminergic Polymorphic Ventricular Tachycardia ( ) Unexplained sudden death in the young ( ) Cardiomyopathy ( ) Arrhythmogenic Right Ventricular Cardiomyopathy ( ) Left Ventricular Noncompaction Cardiomyopathy ( ) Dilated Cardiomyopathy ( ) Dilated Cardiomyopathy and conduction defects ( ) Hypertrophic Cardiomyopathy ( ) Congenital heart disease ( ) Fallots tetralogy ( ) Hypoplastic Left Heart Syndrome ( ) Pulmonary atresia ( ) Transposition of the great vessels ( ) Left Ventricular Outflow Tract obstruction disorders ( ) Isomerism and laterality disorders ( ) Lymphatic disorders ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

5 Meige disease ( ) Milroy disease ( ) Lymphoedema distichiasis ( ) Ciliopathies ( ) Congenital malformations caused by ciliopathies ( ) Bardet-Biedl Syndrome ( ) Joubert syndrome ( ) Rare multisystem ciliopathy disorders ( ) Respiratory ciliopathies ( ) Primary ciliary dyskinesia ( ) Non-CF bronchiectasis ( ) Dermatological disorders ( ) Atopy ( ) Severe multi-system atopic disease with high IgE ( ) Autoimmune skin disorders ( ) Generalised pustular psoriasis ( ) Ectodermal dysplasias ( ) Ectodermal dysplasia without a known gene mutation ( ) Hair Disorders ( ) Familial cicatricial alopecia ( ) Non-syndromic hypotrichosis ( ) Ichthyoses ( ) Autosomal recessive congenital ichthyosis ( ) Keratodermas ( ) Palmoplantar keratoderma and erythrokeratodermas ( ) Familial disseminated superficial actinic porokeratosis ( ) Neurocutaneous disorders ( ) Undiagnosed neurocutaneous disorders ( ) Skin fragility disorders ( ) Epidermolysis bullosa ( ) Peeling skin syndrome ( ) Sun-exposure related conditions ( ) Erythropoietic protoporphyria, mild variant ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

6 Hydroa vacciniforme ( ) Dysmorphic and congenital abnormality syndromes ( ) Kabuki ( ) Kabuki syndrome ( ) RASopathies ( ) Noonan syndrome ( ) Noonan syndrome plus other features ( ) Cardio-facio-cutaneous syndrome ( ) LEOPARD syndrome ( ) Costello syndrome ( ) Legius syndrome ( ) Balanced translocations ( ) Balanced translocations with an unusual phenotype ( ) Limb disorders ( ) VACTERL-like phenotypes ( ) DNA repair disorders ( ) Cockayne syndrome ( ) Non-Fanconi anaemia ( ) Xeroderma Pigmentosum-like disorders ( ) Primary Microcephaly - Microcephalic Dwarfism Spectrum ( ) Autophagy disorders ( ) Vici Syndrome and other autophagy disorders ( ) Dysmorphic disorders ( ) Coarse facial features including Coffin-Siris-like disorders ( ) Familial non-syndromic cleft lip and or familial cleft palate ( ) Syndromic cleft lip and or cleft palate ( ) PHACE(S) syndrome ( ) Radial dysplasia ( ) Fetal disorders ( ) Fetal hydrops ( ) Unexplained monogenic fetal disorders ( ) Endocrine disorders ( ) Adrenal disorders ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

7 Congenital adrenal hypoplasia ( ) Disorders of calcium homeostasis ( ) Familial or syndromic hypoparathyroidism ( ) Growth hormone disorders ( ) IUGR and IGF abnormalities ( ) Rare subtypes of diabetes ( ) Familial young-onset non-insulin-dependent diabetes ( ) Hyperinsulinism ( ) Neonatal diabetes (diagnosed less than 6 months) ( ) Diabetes with additional phenotypes suggestive of a monogenic aetiology ( ) Insulin resistance (including lipodystrophy) ( ) Multi-organ autoimmune diabetes ( ) Obesity syndromes ( ) Significant early-onset obesity with or without other endocrine features and short stature ( ) Gonadal and sex development disorders ( ) Disorders of sex development ( ) Early onset familial premature ovarian insufficiency ( ) Gastroenterological disorders ( ) Gastrointestinal disorders ( ) Infantile enterocolitis and monogenic inflammatory bowel disease ( ) Gastrointestinal epithelial barrier disorders ( ) Growth disorders ( ) Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders ( ) Classical Beckwith-Wiedemann syndrome ( ) Atypical Beckwith-Wiedemann syndrome ( ) Simpson-Golabi-Behmel syndrome ( ) Sotos syndrome ( ) Weaver syndrome ( ) Growth restriction ( ) Silver Russell syndrome ( ) Haematological disorders ( ) Primary immunodeficiency disorders ( ) A- or hypo-gammaglobulinaemia ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

8 Agranulocytosis ( ) Congenital neutropaenia ( ) SCID ( ) Combined B and T cell defect ( ) Inherited complement deficiency ( ) Anaemias and red cell disorders ( ) Early onset pancytopenia and red cell disorders ( ) Congenital anaemias ( ) Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria ( ) Hearing and ear disorders ( ) Non-syndromic hearing loss ( ) Congenital hearing impairment ( ) Auditory Neuropathy Spectrum Disorder ( ) Autosomal dominant deafness ( ) Deafness and congenital structural abnormalities ( ) Bilateral microtia ( ) Familial hemifacial microsomia ( ) Ear malformations with hearing impairment ( ) Metabolic disorders ( ) Specific metabolic abnormalities ( ) Ketotic hypoglycaemia ( ) Lactic acidosis ( ) Cerebral folate deficiency ( ) Undiagnosed metabolic disorders ( ) Congential disorders of glycosylation ( ) Urea Cycle disorders ( ) Hyperammonaemia ( ) Lysosomal storage disorders ( ) Mucopolysaccharideosis, Gaucher, Fabry ( ) Mitochondrial ( ) Mitochondrial disorders ( ) Peroxisomal disorders ( ) Peroxisomal biogenesis disorders ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

9 Other peroxisomal disorders ( ) Disorders of extremely low weight, severe familial anorexia ( ) Severe familial anorexia ( ) Neurology and neurodevelopmental disorders ( ) Motor Disorders of the CNS ( ) Cerebellar hypoplasia ( ) Hereditary ataxia ( ) Early onset dystonia ( ) Hereditary spastic paraplegia ( ) Neurotransmitter disorders ( ) Structural basal ganglia disorders ( ) Inherited Epilepsy Syndromes ( ) Genetic Epilepsies with Febrile Seizures Plus ( ) Familial Genetic Generalised Epilepsies ( ) Familial Focal Epilepsies ( ) Epileptic encephalopathy ( ) Motor and Sensory Disorders of the PNS ( ) Charcot-Marie-Tooth disease ( ) Paediatric motor neuronopathies ( ) Neurodegenerative disorders ( ) Early onset and familial Parkinson's Disease ( ) Complex Parkinsonism (includes pallido-pyramidal syndromes) ( ) Early onset dementia (encompassing fronto-temporal dementia and prion disease) ( ) Amyotrophic lateral sclerosis or motor neuron disease ( ) Neurodevelopmental disorders ( ) Classical tuberous sclerosis ( ) Intellectual disability ( ) Holoprosencephaly ( ) Rhomboencephalosynapsis ( ) Malformations of cortical development ( ) Fetal structural CNS abnormalities ( ) Neuromuscular disorders ( ) Congenital muscular dystrophy ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

10 Congenital myopathy ( ) Congenital myaesthenia ( ) Rhabdomyolysis and metabolic muscle disorders ( ) Distal myopathies ( ) Arthrogryposis ( ) Limb girdle muscular dystrophy ( ) Channelopathies ( ) Skeletal Muscle Channelopathies ( ) Brain channelopathy ( ) Sleep disorders ( ) Kleine-Levin syndrome and other inherited sleep disorders ( ) Cerebrovascular disorders ( ) Moyamoya disease ( ) Parenchymal brain disorders ( ) Intracerebral calcification disorders ( ) White matter disorders ( ) Inherited white matter disorders ( ) Ophthalmological disorders ( ) Anterior segment abnormalities ( ) Corneal abnormalities ( ) Glaucoma (developmental) ( ) Cataracts ( ) Posterior segment abnormalities ( ) Inherited optic neuropathies ( ) Rod-cone dystrophy ( ) Rod Dysfunction Syndrome ( ) Cone Dysfunction Syndrome ( ) Inherited macular dystrophy ( ) Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy ( ) Developmental macular and foveal dystrophy ( ) Ocular malformations ( ) Anophthalmia or microphthamia ( ) Ocular coloboma ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

11 Ocular movement disorders ( ) Infantile nystagmus ( ) Renal and urinary tract disorders ( ) Syndromes with prominent renal abnormalities ( ) Proteinuric renal disease ( ) Familial haematuria ( ) Atypical haemolytic uraemic syndrome ( ) Structural renal and urinary tract disease ( ) Cystic kidney disease ( ) Congenital Anomaly of the Kidneys and Urinary Tract (CAKUT) ( ) Disorders of function ( ) Renal tubular acidosis ( ) Renal tract calcification (or Nephrolithiasis or nephrocalcinosis) ( ) Extreme early-onset hypertension ( ) Unexplained kidney failure in young people ( ) Respiratory disorders ( ) Interstitial lung disorders ( ) Familial pulmonary fibrosis ( ) Vascular lung disorders ( ) Hereditary haemorrhagic telangiectasia ( ) Familial and multiple pulmonary arteriovenous malformations ( ) Rheumatological disorders ( ) Multi-system inflammatory or autoimmune disorders ( ) Periodic fever syndromes and amyloidosis ( ) Juvenile dermatomyositis ( ) Connective tissues disorders ( ) Kyphoscoliotic Ehlers-Danlos syndrome ( ) Skeletal disorders ( ) Skeletal dysplasias ( ) Multiple Epiphyseal Dysplasia ( ) Chondrodysplasia punctata ( ) Thoracic dystrophies ( ) Stickler syndrome ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

12 Osteogenesis imperfecta ( ) Unexplained skeletal dysplasia ( ) Craniosynostosis ( ) Craniosynostosis syndromes ( ) Choanal anomalies ( ) Choanal atresia ( ) Tumour syndromes ( ) Breast and endocrine ( ) Familial breast cancer ( ) Multiple endocrine tumours ( ) Neuro-endocrine Tumours- PCC and PGL ( ) Parathyroid cancer ( ) GI tract ( ) Familial colon cancer ( ) Multiple bowel polyps ( ) Peutz-Jeghers syndrome ( ) Muscle and nerve ( ) Familial rhabdomyosarcoma or sarcoma ( ) Familial tumour syndromes of the central and peripheral nervous system ( ) Neurofibromatosis Type 1 ( ) Skin ( ) Genodermatoses with malignancies ( ) Childhood Tumours ( ) Paediatric congenital malformation-dysmorphism-tumour sydromes ( ) Multiple Primaries ( ) Multiple Tumours ( ) Ultra-rare disorders ( ) Undescribed disorders ( ) Ultra-rare undescribed monogenic disorders ( ) Multi-system groups ( ) Neonatal or paediatric intensive care admission with a likely monogenic disease ( ) Single autosomal recessive mutation in rare disease ( ) RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

13 Introduction Purpose of this document The aim of this document is to provide an up-to-date list of eligibility criteria for conditions approved for recruitment within the Genomics England Rare Diseases Programme. The document replaces the Rare Disease Conditions Criteria v1.4 document released in January Structure and background to eligibility statements For each disease listed we provide an eligibility statement composed of the following key information: 1. Inclusion criteria the clinical features, characteristics or investigations that probands with a given disease must have in order to be eligible for recruitment. 2. Exclusion criteria - the clinical features, characteristics or investigation findings that participants with a given disease must not have in order to be eligible for recruitment. 3. Prior genetic testing this sets out both in general terms, and where appropriate more specifically, the genetic testing which participants with a given disease must have performed prior to recruitment. Each eligibility statement has been informed by at least one clinician specialising in the field and incorporates comments provided during the consultation period with Genomic Medicine Centres. Therefore, we would like to take this opportunity to thank this community for providing their expertise and understanding of complex disorders so generously. Given the rapid progress in the understanding of rare diseases worldwide, it is important that the eligibility statements continue to be reviewed and developed over time in light of new discoveries and changes in clinical practice. Therefore we will continue our engagement with the clinical community throughout the lifetime of the project. Changes since the last release Since the release of version of this document a number of changes have been made. RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

14 New diseases Thirty-one new diseases have been added. They will be recruitable from the time of the informatics release planned for 26 th July 2016: 1. Familial cerebral small vessel disease 2. Unexplained sudden death in the young 3. Milroy disease 4. Lymphoedema distichiasis 5. Non-syndromic hypotrichosis 6. Familial disseminated superficial actinic porokeratosis 7. Familial non-syndromic cleft lip and or familial cleft palate 8. Syndromic cleft lip and or cleft palate 9. PHACE(S) syndrome 10. Radial dysplasia 11. Fetal hydrops 12. Unexplained monogenic fetal disorders 13. Disorders of sex development 14. Early onset familial premature ovarian insufficiency 15. Infantile enterocolitis and monogenic inflammatory bowel disease 16. Gastrointestinal epithelial barrier disorders 17. Silver Russell syndrome 18. Autosomal dominant deafness 19. Familial hemifacial microsomia 20. Ear malformations with hearing impairment 21. Undiagnosed metabolic disorders 22. Congential disorders of glycosylation 23. Neurotransmitter disorders 24. Structural basal ganglia disorders 25. Fetal structural CNS abnormalities 26. Unexplained kidney failure in young people 27. Kyphoscoliotic Ehlers-Danlos syndrome 28. Unexplained skeletal dysplasia 29. Neurofibromatosis Type Neonatal or paediatric intensive care admission with a likely monogenic disease 31. Single autosomal recessive mutation in rare disease RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

15 Changes to disease names The names of a number of disorders (level 4 names) and level 3 names have changed, either to improve accuracy, correct spelling errors or to remove characters that are non-compliant with informatic systems (i.e. < > : " / \? * & which should not be used for new disease names). These are: Old name New name Level 4: Primary ciliary disorders Primary ciliary dyskinesia Neonatal diabetes (diagnosed <6 months) Neonatal diabetes (diagnosed less than 6 months) Significant early-onset obesity +/- other Significant early-onset obesity with or endocrine features and short stature without other endocrine features and short stature Apparent aplastic anaemia / paroxysmal Apparent aplastic anaemia or paroxysmal nocturnal haemoglobinuria nocturnal haemoglobinuria Congenital hearing impairment Congenital hearing impairment (profound/severe) Peroxisomal disorders (other) Other peroxisomal disorders Genetic Epilepsies with Febrile Seizures Genetic Epilepsies with Febrile Seizures Plus (GEFS+) Plus Amyotrophic lateral sclerosis/motor Amyotrophic lateral sclerosis or motor neuron disease neuron disease Leber Congenital Amaurosis / Early-Onset Leber congenital amaurosis or early-onset Severe Retinal Dystrophy severe retinal dystrophy Anophthalmia/microphthamia Anophthalmia or microphthamia Renal tract calcification (or Renal tract calcification (or Nephrolithiasis Nephrolithiasis/nephrocalcinosis) or nephrocalcinosis) Familial tumour syndromes of the central Familial tumour syndromes of the central & peripheral nervous system and peripheral nervous system Familial Non-syndromic cleft lip/ familial Familial non-syndromic cleft lip or familial cleft palate cleft palate Syndromic cleft lip and/or cleft palate Syndromic cleft lip and or cleft palate Level 3: Alopecias Hair Disorders Other dysmorphic syndromes Dysmorphic disorders Multi-system inflammatory/autoimmune disorders Multi-system inflammatory or autoimmune disorders RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

16 Changes to clinical inclusion and exclusion criteria Changes have been made to the clinical inclusion and/or exclusion criteria in 42 existing diseases: 1. Familial Thoracic Aortic Aneurysm Disease 2. Brugada syndrome 3. Long QT syndrome 4. Catecholaminergic Polymorphic Ventricular Tachycardia 5. Arrhythmogenic Right Ventricular Cardiomyopathy 6. Left Ventricular Noncompaction Cardiomyopathy 7. Dilated Cardiomyopathy 8. Dilated Cardiomyopathy and conduction defects 9. Hypertrophic Cardiomyopathy 10. Familial hypercholesterolaemia 11. Familial young-onset non-insulin-dependent diabetes 12. Severe familial anorexia 13. Autosomal dominant deafness 14. Hereditary ataxia 15. Hereditary spastic paraplegia 16. Early onset and familial Parkinson's Disease 17. Complex Parkinsonism 18. Early onset dementia 19. Amyotrophic lateral sclerosis or motor neuron disease 20. Rhabdomyolysis and metabolic muscle disorders 21. Classical tuberous sclerosis 22. Brain channelopathy 23. Kleine-Levin syndrome and other inherited sleep disorders 24. Proteinuric renal disease 25. Familial haematuria 26. Atypical haemolytic uraemic syndrome 27. Cystic kidney disease 28. Familial pulmonary fibrosis 29. Osteogenesis imperfecta 30. Familial breast cancer 31. Multiple endocrine tumours 32. Neuro-endocrine Tumours- PCC and PGL 33. Parathyroid cancer 34. Familial colon cancer 35. Multiple bowel polyps 36. Peutz-Jeghers syndrome 37. Familial rhabdomyosarcoma or sarcoma RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

17 38. Familial tumour syndromes of the central & peripheral nervous system 39. Paediatric congenital malformation-dysmorphism-tumour sydromes 40. Genodermatoses with malignancies 41. Multiple Tumours 42. Ultra rare disorders Changes to prior testing requirements affecting all diseases Since the last release the core text regarding prior genetic testing has been changed in all diseases. Previously, prior genetic testing requirements specified that all genes with a >10% diagnostic yield should be tested before recruitment. This has been changed in all diseases to require prior testing of genes in line with local standard practice. Specific exceptions to the generic prior testing requirements In addition to the above change, specific changes have been made to the prior genetic testing requirements in a number of specific disorders. In three, as part of an experimental programme, recruitment is preferred in parallel with standard genetic testing: 1. Undiagnosed metabolic disorders 2. NICU or PICU admission with a likely monogenic cause 3. Unexplained monogenic fetal disorders. In others, to reflect disease-specific issues, additional guidance has been given about testing that should be carried out prior to recruitment: 1. Neonatal diabetes 2. Early Onset Familial Premature Ovarian Insufficiency 3. Charcot-Marie-Tooth disease 4. Congenital hearing impairment 5. All of the DNA repair disorders 6. Classical Beckwith-Wiedemann syndrome/atypical Beckwith-Wiedemann syndrome 7. Silver-Russell syndrome 8. Hereditary ataxia 9. All of the inherited tumour syndromes RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

18 Other changes to the rare diseases programme In parallel to the changes to eligibility criteria, a number of changes have been made that are relevant to recruitment to the rare disease programme. These are set out in detail elsewhere but are summarised briefly here for the benefit of those recruiting to the programme. 1. Probands can now be resident in England, Scotland, Northern Ireland or Wales as long as they are under the care of the NHS in England. 2. Collection of omics bloods are optional in the rare disease programme until at least September Unaffected relatives can be recruited using telephone consent and stored or postal DNA can be used as set out in the Project sampling handling guidance. 4. From the 26 th July informatics release, revised HPO questionnaires will go live. These reduce the size of the largest 40% of the models by 45%. RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

19 Rare Disease Conditions Criteria Cardiovascular disorders ( ) Arteriopathies ( ) Familial Hypercholesterolaemia ( ) Familial Hypercholesterolaemia eligibility ( ) Level 3 Title Arteriopathies ( ) Level 4 Title Familial Hypercholesterolaemia ( ) Familial Hypercholesterolaemia inclusion criteria ( ) Lipid levels either pre-treatment or highest on treatment: Simon Broome criteria definite familial hypercholesterolaemia : Abnormal lipids: -Total cholesterol > 6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR -Total cholesterol >7.5 mmol/l (290 mg/dl), or LDL cholesterol above 4.9 mmol/l (190 mg/dl) in an adult AND -Tendon xanthomas (TX) in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt) OR Abnormal lipids: -Total cholesterol > 6.7 mmol/l (260 mg/dl), or LDL cholesterol above 4.0 mmol/l in a child < 16 years, OR -Total cholesterol >8.5 mmol/l, or LDL cholesterol above 5.5 mmol/l in an adult AND - Family history of myocardial infarction below age of 50 in 2nd degree relative or below age 60 in 1st degree relative, OR - Family history of raised cholesterol: >7.5 mmol/l in adult 1st or 2nd degree relative or > 6.7 mmol/l in child or sibling under 16 AND Polygenic risk 12-SNP gene score in the bottom two quartiles 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. RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

20 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 Hypercholesterolaemia exclusion criteria ( ) Secondary causes of elevated LDL-C. Patients will only be eligible who have elevated LDL-C on measures taken on a fasting blood sample and after secondary causes of hyperlipidaemia have been excluded. Recessive inheritance. Families showing a recessive pattern of inheritance will not be recruited Individuals with a fasting plasma Triglyceride level of over 2.5mmol/l will be excluded. Familial Hypercholesterolaemia prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LDLR, APOB and PCSK9 Polygenic risk 12-SNP gene score RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

21 Familial cerebral small vessel disease ( ) Familial cerebral small vessel disease eligibility ( ) Level 3 Title Arteriopathies ( ) Level 4 Title Familial cerebral small vessel disease ( ) Familial cerebral small vessel disease inclusion criteria ( ) 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 ( ) Causes of white matter disease other than cerebral small vessel disease (e.g. multiple sclerosis, vasculitis, leukodystrophy). Cases with NOTCH3 mutations RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

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

23 Connective Tissues Disorders and Aortopathies ( ) Familial Thoracic Aortic Aneurysm Disease ( ) Familial Thoracic Aortic Aneurysm Disease eligibility ( ) Level 3 Title Connective Tissues Disorders and Aortopathies ( ) Level 4 Title Familial Thoracic Aortic Aneurysm Disease ( ) Relevant Diseases: - Familial Thoracic Aortic Aneurysm and dissection - Thoracic aortopathy < 50 years with no other established risk factors - Clinically diagnosed Marfan syndrome with no FBN1 mutation - Loeys-Dietz syndrome and Loeys-Dietz syndrome like conditions - Mutation negative Congenital Contractural Arachnodactyly (Beals syndrome) Familial Thoracic Aortic Aneurysm Disease inclusion criteria (Conditions) ( ) - patients suspected to have the above conditions 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 Thoracic Aortic Aneurysm Disease exclusion criteria: ( ) - Sporadic thoracic aortopathies with risk factors - Family history with no affected proband to test Familial Thoracic Aortic Aneurysm Disease prior genetic testing genes: ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

24 practice: - Loeys-Dietz syndrome TGFBR1 and TGFBR2 - Marfan Syndrome FBN1 - Congenital Contractural Arachnodactyly FBN2 - Isolated familial thoracic aortic aneurysms and dissection - ACTA2 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

25 Cardiac arrhythmia ( ) Brugada syndrome ( ) Brugada eligibility ( ) Level 3 Title Cardiac arrhythmia ( ) Level 4 Title Brugada syndrome ( ) Relevant diseases: - Brugada syndrome Brugada inclusion criteria (clinical diagnosis) ( ) Brugada syndrome diagnosed according to criteria*: - ST segment elevation with type I morphology>= 2 mm in >= 1 lead among the right precordial leads V1,V2 positioned in the 2nd, 3rd, or 4th intercostal space occurring spontaneously. OR - a type I ECG morphology as above following a provocative drug test with intravenous administration of Class I antiarrhythmic drugs. AND one or more of the three criteria below: a family history of: - premature sudden death (<40 years old) or autopsy negative sudden death <65 years old: the sudden arrhythmic death syndrome (SADS) AND/OR - other relatives with a diagnosis of BrS (spontaneous or drug-induced; symptomatic or asymptomatic) AND/OR - survivor of cardiac arrest with a spontaneous type I ECG pattern (constant or intermittent), to be recruited as a trio with parents who have been tested for BrS with normal results * Heart Rhythm Society/European Heart Rhythm Association 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. Brugada exclusion criteria (unclear diagnosis) ( ) - Unclear diagnosis or history suggestive of a non-genetic cause RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

26 - Any Brugada syndrome mutation positive (if clearly pathogenic) Brugada prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: SCN5A RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

27 Long QT syndrome ( ) Long QT Syndrome eligibility ( ) Level 3 Title Cardiac arrhythmia ( ) Level 4 Title Long QT syndrome ( ) Relevant diseases: - Long QT syndrome Long QT inclusion criteria ( ) LQTS diagnosed according to criteria*: - In the presence of an LQTS risk score >= 3.5 in the absence of a secondary cause for QT prolongation AND/OR - In the presence of a corrected QT interval for heart rate using Bazett s formula (QTc) >= 500ms in repeated 12 lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation. AND/OR - In the presence of a QTc between 480 and 499ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation in the absence of a pathogenic mutation. AND either one of the two criteria below: - A family history for LQTS with other affected family DNA and phenotype available (at least three over three generations) for linkage studies. OR - Trio of unaffected parents and severely affected child available (sporadic or recessive) * Heart Rhythm Society/European Heart Rhythm Association 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 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

28 should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs. Long QT exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause - Any LQTS mutation positive (if clearly pathogenic) Long QT syndrome prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - KCNQ1, KCNH2 and SCN5A RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

29 Catecholaminergic Polymorphic Ventricular Tachycardia ( ) Catecholaminergic Polymorphic Ventricular Tachycardia eligibility ( ) Level 3 Title Cardiac arrhythmia ( ) Level 4 Title Catecholaminergic Polymorphic Ventricular Tachycardia ( ) Relevant diseases: - Catecholaminergic polymorphic ventricular tachycardia (CPVT) Catecholaminergic Polymorphic Ventricular Tachycardia inclusion criteria ( ) CPVT diagnosed according to criteria*: - In the presence of a structurally normal heart, normal ECG, and unexplained exercise or catecholamine induced bidirectional VT or polymorphic ventricular premature beats (VPBs) or VT in an individual younger than 40 years. OR - In the presence of a structurally normal heart and coronary arteries, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic VPBs or VT in an individual older than 40 years. AND either one of the two criteria below: - A family history for CPVT with other affected family DNA and phenotype available (at least three over three generations) for linkage studies. OR - Trio of unaffected parents and severely affected child available (sporadic or recessive) * Heart Rhythm Society/European Heart Rhythm Association 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 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

30 metrics applied to GMCs. Catecholaminergic Polymorphic Ventricular Tachycardia exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause - Any CPVT mutation positive (if clearly pathogenic) Catecholaminergic Polymorphic Ventricular Tachycardia prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: CPVT, RYR2 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

31 Unexplained sudden death in the young ( ) Unexplained sudden death in the young eligibility ( ) Level 3 Title Cardiac arrhythmia ( ) Level 4 Title Unexplained sudden death in the young ( ) Unexplained sudden death in the young inclusion criteria ( ) Sudden death at age less than or equal to 40 (including Sudden Infant Death Syndrome), AND No diagnosis established on post mortem examination, AND Absence of a pre-existing condition to explain the death. Parents should be recruited under this category in paediatric cases if available In adult cases the deceased individual should be recruited as a singleton; if surviving relatives have a phenotype which points to a particular condition, they should be the focus of further investigation or recruitment to the programme. Surviving relatives must be available to provide appropriate consent. Unexplained sudden death in the young exclusion criteria ( ) Death in the context of a known diagnosed disease or accident Cause of death determined by post mortem examination No post mortem examination carried out No DNA or frozen tissue stored at post mortem. Unexplained sudden death in the young prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: No genes listed RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

32 Cardiomyopathy ( ) Arrhythmogenic Right Ventricular Cardiomyopathy ( ) Arrhythmogenic Right Ventricular Cardiomyopathy eligibility ( ) Level 3 Title Cardiomyopathy ( ) Level 4 Title Arrhythmogenic Right Ventricular Cardiomyopathy ( ) Relevant diseases: - Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Dilated cardiomyopathy - Dilated cardiomyopathy and conduction defects Cardiomyopathies inclusion criteria (Plural) ( ) - Patients with a clear diagnosis and at least one affected relative, OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age 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. Cardiomyopathies exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

33 Arrhythmogenic Right Ventricular Cardiomyopathy prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - ARVC - PKP2 - DSP - DSG2 - DSC2 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

34 Left Ventricular Noncompaction Cardiomyopathy ( ) Cardiomyopathies eligibility (Left Ventricular Noncompaction Cardiomyopathy and Hypertrophic Cardiomyopathy) ( ) Level 3 Title Cardiomyopathy ( ) Level 4 Title Left Ventricular Noncompaction Cardiomyopathy ( ) Relevant diseases: - Left ventricular non-compaction cardiomyopathy - Dilated cardiomyopathy - Hypertrophic cardiomyopathy Cardiomyopathies inclusion criteria (Plural) ( ) - Patients with a clear diagnosis and at least one affected relative, OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age 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. Cardiomyopathies exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

35 Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - MYBPC3, MYH7, TNNT2 and TNNI3 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

36 Dilated Cardiomyopathy ( ) Dilated Cardiomyopathy eligibility ( ) Level 3 Title Cardiomyopathy ( ) Level 4 Title Dilated Cardiomyopathy ( ) Cardiomyopathies inclusion criteria (Plural) ( ) - Patients with a clear diagnosis and at least one affected relative, OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age 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. Cardiomyopathies exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause Dilated Cardiomyopathy prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: ABCC9, ACTC1, CSRP3, LMNA, MYH7, PLN, TNNI3, TNNT2, TPM1, TTN, RBM20 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

37 Dilated Cardiomyopathy and conduction defects ( ) Dilated Cardiomyopathy and conduction defects eligibility ( ) Level 3 Title Cardiomyopathy ( ) Level 4 Title Dilated Cardiomyopathy and conduction defects ( ) Relevant diseases: - Dilated cardiomyopathy - Dilated cardiomyopathy and conduction defects Cardiomyopathies inclusion criteria (Plural) ( ) - Patients with a clear diagnosis and at least one affected relative, OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age 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. Cardiomyopathies exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

38 Dilated Cardiomyopathy and conduction defects prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: LMNA RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

39 Hypertrophic Cardiomyopathy ( ) Cardiomyopathies eligibility (Left Ventricular Noncompaction Cardiomyopathy and Hypertrophic Cardiomyopathy) ( ) Level 3 Title Cardiomyopathy ( ) Level 4 Title Hypertrophic Cardiomyopathy ( ) Relevant diseases: - Left ventricular non-compaction cardiomyopathy - Dilated cardiomyopathy - Hypertrophic cardiomyopathy Cardiomyopathies inclusion criteria (Plural) ( ) - Patients with a clear diagnosis and at least one affected relative, OR - Patients with no family history who have a clear diagnosis of primary hypertrophic cardiomyopathy under 40 years of age 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. Cardiomyopathies exclusion criteria ( ) - Unclear diagnosis or history suggestive of a non-genetic cause RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

40 Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - MYBPC3, MYH7, TNNT2 and TNNI3 RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

41 Congenital heart disease ( ) Fallots tetralogy ( ) Fallots tetralogy eligibility ( ) Level 3 Title Congenital heart disease ( ) Level 4 Title Fallots tetralogy ( ) Fallots Tetralogy inclusion criteria ( ) - Patients with Fallot s tetralogy, including pulmonary atresia with ventricular septal defect and double outlet right ventricle (Fallot type), AND one of the following: - A consanguineous family history OR - At least one first degree relative with a structural cardiac abnormality OR - at least one additional extra-cardiac abnormality Congenital Heart Disease exclusion criteria ( ) - Antenatal history suggestive of non-genetic cause - Chromosome analysis abnormal and clearly pathogenic - Clinical diagnosis of a recognised syndrome with known genetic cause Congenital Heart Disease prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

42 - Genome-wide copy number variation testing(e.g. acgh, SNP array or other genomic microarray) - Where the phenotype is recognisable and is caused by 1-2 principle genes, these should have been tested prior to recruitment RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v

43 Hypoplastic Left Heart Syndrome ( ) Hypoplastic Left Heart Syndrome eligibility ( ) Level 3 Title Congenital heart disease ( ) Level 4 Title Hypoplastic Left Heart Syndrome ( ) Hypoplastic Left Heart Syndrome inclusion criteria ( ) - Patients with Hypoplastic Left Heart Syndrome, AND one of the following: - A consanguineous family history OR - At least one first degree relative with a structural cardiac abnormality OR - at least one additional extra-cardiac abnormality Hypoplastic Left Heart Syndrome exclusion criteria ( ) - Antenatal history suggestive of non-genetic cause - Chromosome analysis abnormal and clearly pathogenic - Clinical diagnosis of a recognised syndrome with known genetic cause Congenital Heart Disease prior genetic testing genes ( ) Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - Genome-wide copy number variation testing(e.g. acgh, SNP array or other genomic microarray) - Where the phenotype is recognisable and is caused by 1-2 principle genes, these should have been tested prior to recruitment RARE DISEASE CONDITIONS ELIGIBILITY CRITERIA v