Approach to the Genetic Diagnosis of Neurological Disorders

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1 Approach to the Genetic Diagnosis of Neurological Disorders Dr Wendy Jones MBBS MRCP Great Ormond Street Hospital for Children National Hospital for Neurology and Neurosurgery

2 What is a genetic diagnosis?

3 What is a genetic diagnosis? 2009 NHS National Genetics Education and Development Centre

4 Different Types of Diagnosis Phenotypic Biochemical Histological Genetic Genetic testing is not necessarily required in all genetic diseases

5 Why make a genetic diagnosis?

6

7 Why make a Genetic diagnosis? Guides management There may be specific treatment Gives information about the prognosis and features the individual is at risk of Stops further investigations (which may be invasive and painful) Gives information about recurrence risks and testing in pregnancy Provides an explanation to families and access to disease specific support groups

8 Approach to Diagnosis Before you have started the history: LOOK! Dysmorphic features (features unusual for age and ethnicity) / Look like parents? Skin Gait / Wheelchair bound / Unusual movements Are you dealing with a syndrome or a single system disease?

9

10 Eyebrows: Arched Straight Interrupted Palpebral fissures Downslanting Upslanting Narrow Long Ears Prominent Small Simple

11 Eyebrows: Arched Straight Interrupted Palpebral fissures Downslanting Upslanting Narrow Long Ears Prominent Small Simple

12 Searching on Google

13 Searching on OMIM

14 Kabuki Make up Syndrome Multiple congenital disorder syndrome

15 HPO Terms We need to speak the same language!

16 London Dysmorphology Database

17

18 Key points to look out for in the History Conception history: Infertility / Recurrent miscarriages suggests possible inherited cause for current disorder IVF (ICSI): Increased chance of imprinting disorders (Angleman syndrome / Prader Wili. Pregnancy and birth history: Bleeding Alcohol Medications Be wary of a history of birth trauma in other relatives

19 Family History

20 Case 1 5 year old boy Presented in infancy with febrile seizures and at 18 months old had a seizure after a vaccination Went on to develop multiple seizure types which were resistant to medication Family history: Mother had febrile convulsions as a child and has learning difficulties and has generalised seizures

21 Dravet Syndrome Recurrent febrile and/or afebrile hemiclonic or generalized seizures, or status epilepticus, in a previously healthy infant, followed by appearance of multiple seizure types generally resistant to anti-epileptic drugs 70 80% are caused by SCN1A mutations, 90% of which occur de novo Encodes a sodium channel Guides treatment: Sodium valproate usually tried first

22 Examination Full examination, OFC, height and weight Assessment for features unusual for age and ethnicity Clinical photographs Genetic Counselling

23 Case 2 Infantile spasms and ongoing seizures Acne

24 Pt 1: Further Ix

25 Pt 1: Further Ix

26 Tuberous sclerosis Primary features facial angiofibromas, cortical tuber, retinal astrocytoma, periungual fibromas, subependymal nodule Secondary features Family history, renal cysts, Shagreen patch Tertiary features hypomelanotic macules, dental enamel pits DEFINITE DIAGNOSIS: 1 primary + 2 secondary PROBABLE DIAGNOSIS: 1 secondary + 1 tertiary

27 Tuberous sclerosis Incidence 1: % new mutation 1-2% recurrence risk from germline mosaicism TSC1 (9q) 40-50% families encodes hamartin (tumour suppressor) TSC2 (16p next to PKD1) 50-60% families encodes tuberin

28 Specific Disorders versus syndromic disorders Specific: Peripheral neuropathies Dystonia Epilepsy without learning difficulties Muscular dystrophies Syndromic: Learning difficulties and developmental delay May have congenital abnormalities May have facial features unusual for age and ethnicity

29 Syndromic Disorders Microarray is the first line test Fragile X testing if learning difficulties Unless a specific disorder is suspected

30 Karyotype Array CGH SNP Array Whole Exome sequencing 2009 NHS National Genetics Education and Development Centre

31 Karyotype and Microarray

32 Chromosomal abnormalities Change in number e.g. Trisomy 21 (Down syndrome); 45X (Turner syndrome) Change in structure e.g. translocations; deletions; duplications May be inherited

33 Microarray analysis Detects duplications/deletions High resolution First line investigation for children with unknown diagnosis (apart from newborns) eg multiple congenital abnormalities, developmental delay and dysmorphic EDTA sample and lithium heparin sample

34

35 Interpreting microarray results Often tricky Often need parental samples Review similar cases Review genes in the region Deletions usually more harmful than duplications Big deletions/duplications usually more harmful than small ones We will know more with time

36 Microdeletion syndromes Williams 7q11 Velocardiofacial/ Di George 22q11 Angelman 15q11-13 Prader-Willi 15q11-13 Williams 22q11 Angelman PWS

37 Capillary sequencing (sanger sequencing) Reading the DNA letters of a single gene A negative result may not exclude the diagnosis Not always clear whether a gene change is causative Takes 2-4 months We currently use for disorders we feel are highly likely

38 Genome wide sequencing technologies Whole genome sequencing or exome sequencing Exome: Reading the DNA letters of all the genes Genome: Reading the DNA letters and the bits inbetween

39 Epilepsy EIEE panel 72 gene panel, continuously updated Genes associated with epilepsy Variety of phenotypes Focuses broad testing to relevant genes

40 Genomic Multi-disciplinary Team Meetings (MDTs) Laboratory scientists Clinicians Lab produces variant report Multiple resources used

41 What does whole exome sequencing miss? Triplet repeat disorders Disorders of imprinting Copy number Variants Gestalt Diagnosis Biochemical Tests Karyotype Capillary Sequencing Methylation studies Beginning of diagnosing Genetic disorders Microarray Genome Wide sequencing Now

42 When to refer to Genetics When a syndromic diagnosis is suspected More than one feature Dysmorphic features Multiple family members affected When a genetic diagnosis has been made When families want to discuss recurrence risks If Genetic testing reveals difficult to interpret results If mum is pregnant referral is urgent

43 Genetic counselling Give information What is the condition? Talk about treatment and prognosis Explain inheritance Discuss chance of happening again: For parents, children and other family members

44 Future children: What people want Pre-pregnancy: Egg / sperm donation Pre-implantation genetic diagnosis Age limited, no healthy children Expensive Relatively low success rate Takes a year to set up

45 Future children: What people want During Pregnancy: Non invasive prenatal diagnosis (parents pay) Chorionic villus sampling Amniocentesis NIPD CVS Amniocentesis

46 Future children: What people want No Intervention: Proceed with pregnancy Testing / Support at birth Palliative care

47 Take home messages Don t forget the basics Microarray and fragile X Good family history Look for dysmorphic features Genome wide sequencing is a reality Interpreting variants from Genome wide sequencing is challenging

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