Clinical Genetics

Question 1

describe the characteristics of autosomal dominant inheritance

Answer 1

• Vertical transmission through generations
• Male to male transmission possible
• Males and females equally affected
• Offspring risk is 1 in 2 for an affected parent
• Reduced penetrance and variable expression

Question 2

define penetrance

Answer 2

proportion of people carrying a gene that actually show it

Question 3

what is non-penetrance

Answer 3

• Non-penetrance – the occurrence of an individual being heterozygous for a dominant gene but showing no signs of it
• Non-penetrance
• May have no features of the disease despite being a gene carrier
• May be sex-limited e.g. ovarian cancer may only occur in females

Question 4

what is meant by variable expressivity

Answer 4

• Variable expressivity – variation in the severity of phenotypic features of a gene
• Example: polydactyly – some individuals may have 2 extra fingers, some only 1 but ALL have extra fingers

Question 5

describe the characteristics of autosomal recessive inheritance

Answer 5

• Usually only members of one sibship affected
• Males and females equally affected
• May be associated with parental consanguinity
• Offspring risk is 1 in 4 for carrier parents
• Risk low for offspring of an affected parent
• Disorders usually present in childhood and are severe

Question 6

what type of inheritance is Mucopolysaccharidosis Type I Hurler disease

Answer 6

autosomal recessive inheritance

Question 7

what type of inheritance is albinism

Answer 7

autosomal recessive inheritance

Question 8

characteristics of X-linked recessive inheritance

Answer 8

• Usually only males affected
• Transmitted by males to carrier daughters only
• Carrier females have 1 in 2 risk of affected sons and 1 in 2 risk of carrier daughters

Question 9

give some examples of X-linked recessive diseases

Answer 9

• Duchenne muscular dystrophy
• Haemophilia A and B (factor VIII, IX) • Colour blindness (red – green)
• Hearing loss

Question 10

characteristics of X-linked dominant inheritance

Answer 10

• Transmitted by females to sons and daughters
• Transmitted by males only to daughters
• No male to male transmission
• Both sexes affected but girls affected more often than boys
• Some conditions lethal in affected males often leading to stillbirth or neonatal death

Question 11

Examples of XLD diseases

Answer 11

• Hereditary motor and sensory neuropathy (HMSN) - may also be Dominant or recessive
• Incontinentia pigmenti
• Rare lethal syndromes

Question 12

describe mitochondrial inheritance

Answer 12

• Defined by a single circular double stranded DNA segment
• During zygote formation, the sperm contributes its nuclear DNA but not its mitochondrial DNA
• Matrilineal inheritance as only a maternal contribution
• Only transmitted by females with offspring risk of up to 100% depending on homoplasmy / heteroplasmy
• Both sexes usually affected

Question 13

what is the difference between homoplasmy and heteroplasmy

Answer 13

• Cells contain many mitochondria:
• If the dividing cells that have predominantly mutated cells are passed on - termed Homoplasmy
• If dividing cells are predominantly normal or mixed numbers of mutations, heteroplasmy

Question 14

Characteristics of Multifactorial Inheritance

Answer 14

• Diseases run in families, but with no characteristic pattern of inheritance. May skip generations.
• Risk falls off significantly from first degree to second degree relatives
• Recurrence risk is higher if more than one family member is affected
• Recurrence risk is higher when the proband has a more severe phenotype
• Recurrence risk is higher if the proband is of the less commonly affected sex
• In general, the risk to offspring and siblings of probands is approximately f (f = prevalence of disease in the population)

Question 15

examples of Multifactorial disorders

Answer 15

• Cleft lip (+/- cleft palate; 1/500 - 1/1,000)
• Diabetes (1/10);
• Heart disease or stroke (1/3 to 1/5)
• Spina bifida (1 in 1000)

Question 16

• Comprehend why it is important to consider the ethical reasons for testing (or not testing) children for genetic disease using MEN2A and FAP as examples

Answer 16

• Need to have an effective treatment e.g. childhood cancers (MEN-2, FAP)
• Usually test at ~18 years or over if a ‘late onset disorder’
• May be insurance implications
• Don’t test just because the parents want
to know (as the child may not want to know that he or she has an incurable condition)

Possible to do a genetic test on a child - show that they are predisposed to cancer and therefore treat them before it becomes an issue - can do this for breast cancer and in the MEN-2 case, thyroid

MEN-2 [Multiple Endocrine Neoplasia type II]:
• Medullary thyroid cancer
• C-cell hyperplasia
• Often diagnosis in childhood
• Thyroidectomy is curative

Familial Adenomatous Polyposis Coli (FAP):
• Incidence: ~1/10,000
• Autosomal dominant
• Thousands of polyps
• By age 15, >50% of affected individuals will have multiple polyps - high penetrance
• Mutations in APC gene (Chromosome 5)
- can test for this in childhood and treat

Question 17

• Be able to identify the ethical issues involved in the use of predictive (presymptomatic) testing for untreatable genetic diseases - Huntington disease as an example

Answer 17

clinical features of huntingtons:
• Chorea
• Cognitive dysfunction
• Psychiatric illness
• Average onset early middle life (35 -45 yrs)
• Anticipation - A disease that occurs with increasing severity in subsequent generations.
• Lethargy /inertia
- Relatively selective loss of cells in neurodegeneration
• Greater the expansion, generally worse prognosis and earlier onset of the disease - worse between generations

• No treatment at present
• Presymptomatic gene testing is available

Testing for HD:
• Diagnostic test – confirms diagnosis in symptomatic patient
• Presymptomatic or predictive test: testing an at-risk asymptomatic person – check attitudes to, knowledge of, and experience of HD, and take written consent

Question 18

• Be able to evaluate

the ethical issues surrounding pre- implantation genetic diagnosis

Answer 18

• 8 cell embryo
• Remove 1 cell - test DNA for single gene and chromosomal disorders
• If abnormal, do not implant egg, If normal then implantation
• each disorder needs a licence from the HFEA
• 20-30% “take home baby rate”

Why do pre-implantation diagnosis?
• Parental choice
• May avoid termination of pregnancy for serious abnormalities
• Drawbacks – cost, error, stress, travelling

Question 19

• Be able to evaluate implications and misuse of genetic screening by insurance companies and employers

Answer 19

Employment:
• Better that employer makes the workplace safe than demanding a genetic test
- they shouldn’t ask

Insurance Moratorium:
• Government moratorium currently in place
• Life insurance: no use to be made of genetic test results on policies up to £500,000
• Long-term care insurance, critical cover: No use to be made on policies up to £300,000
• Only one test approved at present – HD gene

Question 20

• Be able to describe the chromosomal basis of inheritance and how alterations in chromosome number or
structure may arise during mitosis and meiosis

• Be able to describe clinical features of common chromosomal disorders
• Be aware of the types of clinical features which suggest a dysmorphic or malformation syndrome
• Be aware of the roles of genes and teratogens in human congenital anomalies

Answer 20

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Question 21

describe the clinical features of Edwards syndrome

Answer 21

Tri 18
❑ Arthrogryposis, rocker- bottom feet, heart defects, IUGR
❑ Early death

Question 22

describe the clinical features of Patau syndrome

Answer 22

Tri 13
❑ Facial clefts, holoprosencephaly, heart defects, polydactyly, scalp skin defects, renal dysplasia
❑ Early death

Question 23

describe mosaicism

Answer 23

An individual or a tissue may contain different populations of cells with different numbers of chromosomes

◼ Typically represents a POST-ZYGOTIC event
◼ Or, may be a consequence of TRISOMY RESCUE – a trisomic cell line may
lose an extra chromosome during mitosis, “rescuing” the karyotype

Question 24

describe Uniparental disomy - UPD

Answer 24

◼ Both copies of a chromosome arising from one parent
◼ E.g. Chromosome 15 maternal UPD in Prader Willi syndrome
◼ Paternal UPD 15 results in Angelman syndrome
◼ Occurs because some genes show parent-of-origin
expression – IMPRINTING
◼ Recurrence risk usually LOW

Question 25

describe the clinical features of Prader-Willi syndrome (Maternal UPD 15, or deletion on the paternal 15)

Answer 25

``` (Maternal UPD 15, or deletion on the paternal 15) ◼ Small for dates ◼ Neonatal hypotonia ◼ Feeding difficulties ◼ Facial dysmorphism ❑ Almond shaped eyes ❑ Tented upper lip ◼ Small hands & feet ◼ Small genitalia in male ◼ Often pale colouring ◼ Hyperphagia in childhood ```

Question 26

describe the clinical features of Angelman syndrome (paternal UPD 15 or deletion on the maternal 15)

Answer 26

``` (paternal UPD 15 or deletion on the maternal 15) ◼ Mental retardation ◼ Little/no speech ◼ Jerky movements ◼ Spontaneous laughter ◼ Characteristic facial features ```

Question 27

what is translocation in chromosomes

Answer 27

◼ Part of one chromosome becomes detached & re-attaches to another chromosome ◼ Arise during meiosis; may be de novo or inherited ◼ Robertsonian translocation ❑ 2 acrocentrics stuck together ❑ Most common: 13;14 ◼ Balanced reciprocal translocation ❑ Simple swap-around of material

Question 28

how would you discuss and assess chromosomal abnormalities

Answer 28

◼ Standard cytogenetics (karyotype) ❑ Well established, but misses subtle abnormalities ❑ Imprecise correlation to the genes involved ❑ VERY labour intensive ❑ NOT a great first line test any more – pickup <3% ◼ Array CGH (comparative genomic hybridisation) ❑ Precise localisation of copy number abnormalities ❑ Gold standard, but will not detect balanced rearrangements ◼ FISH (fluorescence in situ hybridisation) ❑ Useful for known familial abnormalities or high suspicion of specific syndrome ◼ MLPA (multiplex ligand-mediated probe amplification) ❑ PCR technique, rapid, reliable

Question 29

describe the clinical features of Cri du chat syndrome

Answer 29

``` Deletion chromosome 5p – “Cri du chat” syndrome ◼ Microcephaly ◼ Wide mouth ◼ Hypertelorism ◼ Learning disability ◼ Facial dysmorphism ◼ Cat-like cry ```

Question 30

describe the clinical features of DiGeorge syndrome

Answer 30

DiGeorge syndrome (del 22q11) Velocardiofacial syndrome ``` ◼ Cardiac abnormalities ◼ Thymic hypoplasia; T cell abnormalities ◼ Hypocalcaemia ◼ Cleft palate ◼ Prominent ears, micrognathia, cleft palate ◼ Broad nose ◼ Long slender fingers ◼ (Do NOT use the term “CATCH22”) ```

Question 31

describe the clinical features of Williams syndrome

Answer 31

``` ◼ Deletion 7q11 ◼ Hypercalcaemia ◼ Developmental delay ◼ Executive planning deficit ◼ “Cocktail party speech” ◼ Stellate irides (iris) ◼ Supravalvular aortic stenosis ``` (Reciprocal duplication causes autistic traits, straight eyebrows, etc)

Question 32

describe the clinical features of Hereditary Motor & Sensory Neuropathy 1A (Charcot-Marie-Tooth 1A)

Answer 32

``` ◼ Distal neuropathy ◼ Wasting of peroneal muscles ◼ Clawed feet ◼ Sensory disturbances ◼ Duplication of PMP22 gene on chr 17 ◼ Deletion (i.e. one copy) leads to HNPP – hereditary neuropathy with liability to pressure palsies ```

Question 33

describe the clinical features of Marfan syndrome

Answer 33

- Tall; Long limbs - Armspan > height - Lax joints - Arachnodactyly (fingers and toes abnormally long and slender) - Lens dislocation - High-arched palate - Dissecting aortic aneurysm - Gene: FBN1 (chr15)

Question 34

Describe the principles of risk estimation in Mendelian disease & communicating risk to families Summarise the clinical features of common autosomal dominant and autosomal recessive Mendelian diseases using examples e.g. neurofibromatosis, Marfan syndrome; cystic fibrosis Recognise situations where it is important to obtain genetic information and advice and be able to describe ways of obtaining these Understand the distinction between genetic screening and genetic testing Assess the importance of cardiac genetics in prevention of disease Be aware that all cancers are genetic but some individuals are at increased risk Be aware of examples of clinical indicators that suggest an inherited predisposition to cancer e.g. HNPCC, breast cancer, the role of genetic testing (diagnostic & predictive), understand the importance of surveillance in at risk individuals & screening programmes available for hereditary cancer

Answer 34

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Question 35

describe the clinical features of Russell silver syndrome

Answer 35

* IUGR - inter uterine growth restriction * Short stature but normal growth velocity & head circumference * 5th finger clinodactyly * Hemihypertrophy * Dev delay clinical genetics 5 - slide 12

Question 36

describe the clinical features of solos syndrome

Answer 36

* Autosomal dominant, NSD1 gene * Presentation: - Early overgrowth with advanced bone age & tall stature - Large head (macrocephaly), prominent forehead, pointed chin • Sometimes: - Mild/moderate learning difficulties-variable - Cardiac & renal problems clinical genetics 5 - slide 15

Question 37

describe clinical features of Marfan syndrome

Answer 37

* Connective tissue disorder * Fibrillin (FBN1) gene * Involvement of ocular, skeletal & cardiovascular systems * Diagnosis – Ghent criteria skeletal features: • Tall stature, wide arm span • Arachnodactyly - long fingers & toes - clinical genetics 5 - slide 23 ``` other features: • Joint flexibility • Crowded teeth • High arched palate • Scoliosis • Skin straiae ``` * Congenital valve abnormalities * Aortic dissection – patients need screening (cardiac ECHO/MRI) &/- drug treatment or surgery

Question 38

clinical features of Loeys-Dietz syndrome

Answer 38

• Autosomaldominant * Vascular & skeletal involvement * Also dysmorphic * Genes -TGFBR1, TGFBR2, SMAD3 * Some genotype/phenotype correlation (with Marfan), e.g. joint pains - can have bifurcated uvula

Question 39

clinical features of Ehlers-Danlos syndrome (E.D.S.)

Answer 39

• A.D, C.T. disorder * Many subtypes: * Classic – skin hyperextensible, jt hypermobility, abnormal wound healing * Vascular - hypermobility, kyphoscoliosis, progeroid features etc

Question 40

Neurofibromatosis type clinical features

Answer 40

• 1/3000 * NF1 gene, Chromosome 17 * De novo mutation in 50% • Diagnosis: - CALs, freckling, FH etc - Neurofibromata(post- pubertal) - NIH Criteria - clinical diagnosis ``` Complications: • Plexiform neuromas • DevDel/LDs/macrocephaly • Skeletal - scoliosis, tibial pseudarthrosis • High BP - renal artery stenosis ``` • Cancer risks: - Brian – optic gliomas– eyes exam - Phaeochromocytoma–BPyrly - Breast–mammogram yrly from 40s

Question 41

Huntington disease clinical features

Answer 41

``` • Prevalence-10-12/100,000 • Chorea, hand tremor etc - can lead to clumsiness & falls • Cognitive dysfunction • Psychiatric illness – may be presenting complaint • Average onset early 30s-40s ```

Question 42

clinical features of rett syndrome

Answer 42

clinical genetics 5 - slide 50 * 1/10,000 – 1/15,000, females mostly... * MECP2 gene * Around 25 in N.I. * Acquired microcephaly * Seizures * Normal dev 6-18 mths * Regression * Stereotypic hand movements * +/- autistic features * Speech in 6%, poor mobility

Question 43

briefly describe tuberous sclerosis complex (TSC)

Answer 43

• 1 in 5,5000 - ~110 pts in N.I. * Average age at diagnosis = 7.5yrs * 81% diagnosed before 10yrs • 2 genes identified:  TSC1 & TSC2  Autosomal dominant, but 2/3 pts de novo • Mutations in these genes activate the mTOR pathway... - it is a multi system disorder - see clinical genetics 6 slide 20

Question 44

describe how you may be able to early diagnose Tuberous Sclerosis and why is this important

Answer 44

• Fetal scan: - Cardiac rhabdomyomas seen in up to 50% of TS pregnancies - Around 80% with rhabdomyomas have TS * CNS: * 5% TS pts have seizure in 1st month * Brain MRI • Predictive testing if family history ``` Why is early diagnosis important? • Renal – AML surveillance • CNS - epilepsy: - Educate parents on seizure recognition - Early seizure control is linked to better long-term prognosis for IQ & reduction in autistic features - test with regular EEGs - can start anti-epileptics at the right time • Early recognition of ASD/autism ``` can be treated with rapamycin

Question 45

describe the mTOR pathway and its link to tuberous sclerosis - briefly talk about mTOR inhibitors

Answer 45

• Pathway involved in: - Energy release - Regulation of cell growth & size • Normal function: - Hamartin-tuberin form dimer - Dimer causes inhibition of mTOR pathway, so regulatory effect to control & limits cell growth • TSC: - Loss of protein dimer complex leads to activation of mTOR pathway & tumour formation ``` mTOR inhibitors: • TSC & mTORs: - Too rare to have NICE guidelines - Expensive - Require Individual Funding Request • Everolimus licence – for specific conditions at specific ages • Particularly useful for growing tumours in kidneys & brain – shrinkage, plus additional benefits: - Epilepsy - behavioural ```

Question 46

describe spinomuscular atrophy (SMA) and its sub classifications

Answer 46

* Rare neuromuscular disorder * Degeneration of alpha-motor neurons in the anterior horn cells * Progressive muscle weakness & atrophy * Commonest genetic cause of infant mortality * Autosomal recessive – SMN1, 5q13.2 * 1 in 11,000 newborns SMA types: • Continuous spectrum of muscle weakness • Variable, even within families • Weakness – symmetrical, proximal to distal, progressive • Failure to meet milestones +/- regression • Also – tongue fasciculations, hypotonia, reduced/absent reflexes Sub - classification: ``` Type 0: • Prenatal onset • Symptomsfrombirth Type 0 • Nomilestonesachieved, respiratory failure +/- facial diplegia • Death by 6 mths ``` ``` Type 1 - Werdnig-Hoffmann: • Symptoms before 6 months • Oral weakness, dysarthria • Sit with support only • +/- joint contractures, bell- shaped chest • Median age to: - Ventilation-10.5mths - Death–13.5mths ``` ``` Type 2 - Dubowitz disease: • Symptoms from 6-18 mths • Able to sit unaided – loose ability by teens • Can not walk • +/- tremor in fingers, scoliosis • 70% survive to 3rd decade ``` Type 3: • Can learn to walk: - Type 3a – onset <3yrs, 73% chance of walking after 10yrs - Type 3b – onset >3yrs, 97% chance of walking after 10yrs • Compatible with normal lifespan ``` Type 4: • Adulthoodonset • Diffuse,symmetrical,proximal muscle weakness • Absent/decreased deep muscle reflexes • Normal lifespan ```

Question 47

describe how Antisense oligonucleotides (ASO) can be used to help treat Spinomuscular Atrophy (SMA)

Answer 47

* Identificationofintron-splicing silencer sequence, N1, in SMN2 intron 7 * Antisenseoligonucleotides (ASO) – bind to N1 in pre- mRNA – promotes exon 7 inclusion * Full length SMN protein produced * Approved for types 1 & 2 * Allows motor milestone acquisition * Does not cross blood brain barrier so intrathecal injection ``` In older patients: • Type 3: • No double-blind, placebo-controlled trials • Some improvements observed • Type 4: • No patients treated ``` Very expensive

Question 48

briefly describe Duchenne muscular dystrophy

Answer 48

• X-linked recessive * High new mutation rate & often no FH * ~1/3 de novo in child, 1/3 de novo in mother, 1/3 mat grandmother * Diagnosis 3-5yrs * Wheel chair 12yrs * Teens–cardiac problems * 2nd-3rd decade – death from cardiac/resp failure WIKI: Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms.

Question 49

briefly describe Becker Muscular Dystrophy

Answer 49

* Milder form than Duchenne Muscular Dystrophy * Wheelchair from 2nd/3rd decade * Only symptom may be cardiomyopathy * Can live to 8th/9th decade WIKI: Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin.