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Clinical Applications of Genomics in Rare Disease and Cancer > Adult General Genetics > Flashcards

Adult General Genetics Flashcards

1
Q

What is a primary cause of death

A

Sudden cardiac arrest

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2
Q

What are some structural cardiac abnormalities

A

Hypertrophic, arrhythmogenic, congenital (inc. Marfan), mitral valve prolapse/aortic stenosis

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3
Q

What are some electrical cardiac abnormalities

A

Wolff Parkinson White syndrome, congenital long QT (incl. Brugada syndrome), catecholaminergic polymorphic ventricular tachycardia (CPVT)

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4
Q

What are some acquired cardiac abnormalities

A

Infection (myocarditis), trauma (commotio cardis), toxicity (drugs), environment (hypo/hyperthermia)

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5
Q

What are 3 examples of cardiac disease types

A

Congenital heart disease
Cardiac muscle disease
Cardiac rhythm disturbance

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6
Q

What are some examples of cardiac abnormalities

A

Cardiac anatomy abnormalities - congenital heart disease, valvular heart problem, aortopathies

Cardiac blood supply abnormalities - coronary heart disease

Cardiac conduction abnormalities

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7
Q

Where should the heart be located

A

To the left

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8
Q

What are common causes of congenital heart disease

A

Chromosome
Trisomy 21 - atrio-ventricular septal defects
Di George syndrome (22q11.2 microdeletion) - Conotruncal disorders e.g. truncus arteriosus

Single gene disorders
Syndromic - CHARGE, Cornelia De Lange
Non-syndromic - NKX2-5 and MYH6 (can cause ASD also)

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9
Q

What are ciliopathies

A

Group of conditions with a wide number of abnormalities

Ahlstrom syndrome - lead to dilated cardiomyopathy

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10
Q

How is the foetal circulation different to the postnatal circulation

A

Oxygen tension in the umbilical vein is less than post-natal oxygenation from the lungs

Blood from umbilical vein flows into the ductus venosus which reduces the pressure > enters right atrium flows through foramen ovale and then diverted via the ductus arteriosus

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11
Q

What happens to the ductus venosus and arteriosis postnatally

A

The ductus venosus and arteriosus are artefacts post-natally

Closure of the ductus arteriosus becomes the ligamentum arteriosum by a decrease in prostaglandin

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12
Q

What are the three types of cardiomyopathy

A

Hypertrophic

Dilated

Arrhythmogenic

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13
Q

What is hypertrophic cardiac myopathy

A

Hypertrophic - thickening of the ventricular walls

Involves mutations in sarcomeric proteins

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14
Q

What is dilated cardiac myopathy

A

Dilated - most common cause for heart transplant, heart muscle fails, more non-genetic causes

Involves mutations in cytoskeletal proteins /sarcomeric

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15
Q

What is arrhythmogenic cardiac myopathy

A

Arrhythmogenic - aka arrhythmogenic right ventricular cardiomyopathy, but it affects both ventricles

Involves mutations in desmosomal proteins

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16
Q

What is used to detect the difference between cardiomyopathies

A

NGS panels as they are multigenic with overlap between phenotypes

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17
Q

Describe the two types of hypertrophic cardiomyopathy

A

Apical and septal, where apical is less likely to be due to genetic causes

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18
Q

What is the clinical presentation of hypertrophic cardiomyopathy

A

Syncope, chest pain, shortness of breath, sudden death

Syncope = fainting, due to ischaemia caused by hypertrophy of the ventricles, increased pressure upon contraction leading to chest pain and fainting especially during exercise

Hypertrophy can lead to myocardial disarray - becoming pro-arrhythmogenic

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19
Q

What can be seen on an ECG when looking for hypertrophic cardiomyopathy

A

Septal hypertrophy - tall R waves and abnormal Q wave

Apical hypertrophy - T wave inversion

Multifactorial - associated with diabetes, underlying cardiac diseases

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20
Q

What genes are involved in hypertrophic cardiomyopathy

A

Majority are those involved with the sarcolemma e.g. myosin, actin, troponin

Mysoin - MYH7 = 35% and MYBPC = 35%

Troponin I/T/C - TNNC1/2/3

Involved in calcium metabolism, more involved with rhythm disturbance at an early stage

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21
Q

What percentage of dilated cardiomyopathy is genetic

A

30-40%

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22
Q

What are some causes of dilated cardiomyopathy

A

Other aetiologies - ischaemic, drug Induced, alcohol, myocarditis (inflamed heart muscle), sarcoidosis (lumps of inflammatory cell/granulomata), autoimmune disease, post-partum

Post-partum and alcohol = predisposing due to existing titin mutations

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23
Q

What is the clinical presentation of dilated cardiomyopathies

A

Shortness of breath, cough, swelling of ankles, syncope, fatigue, arrhythmias

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24
Q

What genes are involved in dilated cardiomyopathy

A

Titin gene - aka connectin, molecular spring connecting the filaments between Z-lines
May just be a risk factor
A major player in dilated cardiomyopathy

RBM20
RMB20 facilitates the alternative splicing of various cardiac genes including titin and CPVT
Leads to dilated cardiomyopathy and arrythmia’s

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25
Q

What are the characteristics of arrhythmogenic cardiomyopathy

A

Fibrosis/fatty infiltration of right ventricle BUT frequently involves the left ventricle

May present with DCM phenotype

1st symptom is commonly sudden death on exercise

Later presentation with Cardiac failure

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26
Q

What genes are involved in arrhythmogenic cardiomyopathy

A

Desmosome proteins, which adhere cardiac cells together, and allows messaging between the cells
Faulty messaging can lead to fibrosis

Lamin A/C - supports the nuclear membrane
Mutations in these genes causes nucleus to collapse causing cell death

Desmin - protein that fixes the sarcomere to other structures in the cardiac cell

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27
Q

What can treat arrhythmogenic cardiomyopathy

A

Implantable devices (pacemaker) treats rhythm while implantable defibrillator protects and only acts when needed

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28
Q

What are some cardiomyopathy genes and their inheritance patterns

A

Autosomal dominant with reduced penetrance - MYH7 in HCM

Age related penetrance - MYBPC3

May present from foetal - old age MYH7

Autosomal recessive - Pompe’s

X-linked recessive Fabry’s GLA

X-linked Dominant with male lethality

X-linked Dominant - Danon LAMP2

Oligogenic

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29
Q

What are channelopathies are the three types

A

Primary rhythm disturbances

Long QT

Brugada Syndrome

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

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30
Q

What is Q-T interval

A

Q = when the heart is full while T = when the heart contracts/empties

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31
Q

What are the three types of long QT syndrome

A

LQTS1 - K - loss of function - 30-35% - easily treated with beta blockers

LQTS2 - K - loss of function - 25-30% - mutation in KCNH2

LQTS3 - Na - gain of function - 5-10% - mutation in SCNA, worrying as it is triggered by sleep

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32
Q

What is Brugada syndrome

A

Abnormal ECG - identified in A&E when individual is sick

Sodium channel blocker may trigger the abnormal pattern for investigation
Beta blockers don’t work, so may need ICD (implantable cardioverter-defibrillator)

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33
Q

What is CPVT

A

Rare but highly malignant, 30% with mutation in RYR2

Calcium channel for contraction, mutation may cause leakage of calcium especially under adrenaline

Recurrent attacks upon exercise
Resting ECG is normal, with a bidirectional alternating VT

Can be treated partially with beta blockers, but ICD can be fatal due to shock causing adrenalin

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34
Q

What are some neurogenetic disorders and diseases

A

Obvious ones - epilepsies, neurodegenerative disease, movement disorders, neurofibromatoses

Less obvious - mitochondrial disease, channelopathies,

Diseases - Charcot-Marie Tooth Disease, Muscular Dystrophies, ALS/MND

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35
Q

Why is making a diagnosis important

A

To provide an explanation

To allow screening/monitoring for other symptoms

Guide treatments
E.g. whether a person with epilepsy should have sodium valproate or not (mitochondrial disease?)

There may be implications for other family members

36
Q

How can you make diagnoses

A

Consider non-genetic and genetic causes - family history, are there other associated features etc.

Diagnostic Testing
Single Gene Testing
Panel Testing
Whole Exome/Genome Sequencing

37
Q

If a baby is born with joint problems, reduced movement and the mother has difficulties in loosening grip what can be the cause

A

Myotonic dystrophy

38
Q

What are the two types of myotonic dystrophy

A

Type 1
4 different subtypes - mild, classical, juvenile, congenital
CTG Triplet repeat disorder in DMPK gene

Type 2
Typically proximal muscle weakness, variable myotonia, no congenital form
CCTG repeat in CNBP gene

39
Q

What are the major effects of myotonic dystrophy type 1

A

Cognitive function - intelligence, behaviour, psychological disorders, excessive daytime sleepiness

Vision - cataracts, retinal damage

Endocrine system - diabetes, low thyroid hormone levels

Respiratory system - breathing difficulties, aspiration, sleep apnoea, high risk for pneumonia

Reproductive system
Men - low testosterone, ED, testicular failure, gonadal atrophy
Women - weakened uterine muscle, pregnancy complications and gynaecological problems

Cardiovascular system - heart condition abnormalities, arrythmias, cardiomyopathy

GI tract - swallowing issues, abdominal pain, IBS, constipation/diarrhoea, poor nutrition, weight loss

Muscle - weakness, wasting/atrophy, myotonia, pain

Also - skin bone and immune anomalies

40
Q

What symptoms may a neonate with congenital myotonic dystrophy have

A

Poor motivation, concentration, ADHD, ASD, mental retardation or delays, speech problems

Swallowing and feeding difficulties, bowel and bladder delays

Possible club feet, tight heel cords, AFO or braces

Poor head control, ear infections, facial weakness

Respiratory distress, may have breathing problems at birth, mechanical ventilation
Floppy baby, poor muscle tone

41
Q

What is the pathophysiology of myotonic dystrophy

A

CTG expansion in non-coding region of DMPK

Imperfect double stranded hairpin RNA structure

Toxic RNA gain of function
Gene missplicing
Transcriptional dysregulation
Abnormal protein translation
Activation of cellular stress pathways - mitochondrial and metabolic
42
Q

What is the molecular diagnosis of myotonic dystrophy

A

PCR detects alleles containing 5 and 125 CTG repeats and can be accurately sized

TP-PCR uses 3 primers and creates products of differing lengths with large repeats being detectable but not sizeable

Southern blotting used for accurately sizing DNA fragments

43
Q

What is anticipation (triplet repeat)

A

Unstable/dynamic expansions therefore can increase in size in next generation

Anticipation
This occurs in repeat expansion disorders, as the repeat region grows
Symptoms can present earlier and earlier in subsequent expansion

Instability may depend on parent of origin - maternal in MD, paternal in huntington’s

General correlation between size of expansion and severity of the disorder

44
Q

Is the triple expansion repeat instability of myotonic dystrophy influenced more maternally or paternally

A

Maternally

45
Q

Is the triple expansion repeat instability of Huntington’s disease influenced more maternally or paternally

A

Paternally

46
Q

What us Huntington’s disease

A

Adult onset neurodegenerative disease, dominantly inherited C-A-G triplet repeat expansion

Main features are chorea, dementia and neuropsychiatric disease

Antisense oligonucleotides can target RNA and prevent protein transcription - also used in spinal muscular atrophy

47
Q

What is spinal muscular atrophy caused by

A

Recessive CNV in SMN1 - loss of protein production

The SMN2 gene only produces a small amount of functional protein, genetic artefact, oligonucleotides can help stimulate the 90% that usually does not get translated into protein

Causes problems with muscles in neonatal period, can lead to muscular weakness and death

48
Q

What is the genetic risk of Alzheimer disease

A

Approximately 25% of all AD is familial (i.e., ≥2 persons in a family)

Of which 95% is late onset ( >60-65 years), 5% is early onset (<65 years)

49
Q

What are the symptoms of Alzheimers disease

A

Slowly progressive memory difficulties

Confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations

Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism

50
Q

How can you diagnose Alzheimer’s disease

A

Clinical signs - slowly progressive dementia

Neuroimaging
Gross cerebral cortical atrophy on CT or MRI
Diffuse cerebral hypometabolism on PET
Cerebrospinal fluid (CSF) - decreased Aβ amyloid 42 and increased tau

Neuropathological Findings at postmortem – 80-90% concurrence with clinical diagnosis

51
Q

What are the causes of early onset familial Alzheimer’s disease

A

Mean Onset <65 years, Autosomal Dominant

Chance of finding a mutation in a simplex case is LOW <6%
APP (10-15%) 1.4%
PSEN1 (30-70%) 4%
PSEN2 (<5%)1%
Other loci
52
Q

What is a key Alzheimer’s disease genetic risk factor

A

ApoE

53
Q

What does the apoE gene do

A

ApoE encodes a polymorphic glycoprotein expressed in liver, brain, macrophages, and monocytes

ApoE participates in transport of cholesterol and other lipids
Involved in neuronal growth, repair response to tissue injury, nerve regeneration, immunoregulation, and activation of lipolytic enzymes

54
Q

What are the apoE variants

A

The APOE gene contains three major allelic variants at a single gene locus (ɛ2, ɛ3, and ɛ4)
Encodes different isoforms (ApoE2/3/4) that differ in two sites of the amino acid sequence.

55
Q

What is the risk variants associated with ApoE

A

The APOE ɛ4 allele increases risk in familial and sporadic early-onset and late-onset AD
○ x3 risk for APOE ɛ34, x15 for APOE ɛ44, 40–65% of AD patients are ɛ4 carriers

The effect of APOE ɛ4 accounts for 27.3% of the estimated disease heritability of up to 80%

The APOE ɛ2 allele is thought to have a protective effect
20–25% of the general population carries one or more ɛ4 alleles

56
Q

How significant are the apoE risk variants

A

Up to 75% of individuals heterogeneous for APOE ɛ4 do not develop AD during life

Up to 50% of people with AD do not carry the high-risk ɛ4 allele

The case for testing and the risks associated with other genes is even weaker

57
Q

Why is finding risk variants important

A

Insight into pathogenic mechanisms

Druggable targets

Risk stratification in clinical trials

There is limited clinical utility in the context of the individual patient

58
Q

What is the aorta, describe its pathing

A

Main blood vessel/artery leading out of the heart, exiting the left ventricle and loops out into an arch

The arch leads upwards to supply the head, neck and arms

The descending aortas becomes the abdominal aorta once it passes the diaphragm and innovates everything else including the kidneys and legs

Descending aorta can be divided into the thoracic and abdominal

59
Q

What are the three aortopathies categories (not diseases/syndromes)

A

Aortic aneurysm
Aortic dissection
Aortic regurgitation

60
Q

What is an aortic aneurysm

A

The aorta is pretty smooth, slightly dilateds it leads out of the heart

Aneurysm = pathological dilatation

Most common site being in the abdominal aorta, mainly due to environment
Burst can be fatal - treated by implanting a graft/mechanical valve/tube

61
Q

What is an aortic dissection

A

A partial tear in the wall of the aorta

The aorta has two layers, blood accumulates into the second layer forming a ‘false lumen’

At this point an aneurysm can become symptomatic
E.g. compression on nerve, push on oesophagus

62
Q

What is an aortic regurgitation

A

Aortic value fails to close, allowing blood to leak backwards
Blood re-enters into the left ventricle

Can be due to primary pathology in the valve itself
Or due to aneurysms, because of the dilatation pulling the valves apart

63
Q

What are examples of aortopathy diseases/syndromes

A

Marfan syndrome

Loeys-Dietz syndrome

Collagenopathies

Non-syndromic thoracic aortic aneurysm - harder to identify as there are no obvious external features

64
Q

What type of disorder is Marfan syndrome

A

Connective tissue disorder

65
Q

How do males and females vary with Marfan syndrome

A

Incidence is same

Men have shorter life expectancy

66
Q

What is the inheritance pattern of Marfan syndrome

A

AD, with variable expressivity

67
Q

What is the common gene involved in Marfan syndrome

A

Fibrillin-1 (FBN1) - a microfibril glycoprotein in elastic/non-elastic tissues, part of extracellular matrix

~25% de novo mutations / ~75% inherited and > 97 different mutations

Diagnostic yield 66-91% of cases

68
Q

What are the features of marfan syndrome

A

Long limbs/fingers, downslant eyes, flattened cheek bones, lower jaw pushed back, deep set eyes

69
Q

What symptoms and systems are affected by Marfan syndrome

A

Cardiac - mitral valve prolapse, aortic root dilation

Head/neck - myopia (nearsightedness), lens dislocation (ectopia lentis), high palate and crowded dentition

Chest - spontaneous pneumothorax

Neurologic - dural ectasia

Skin - stretch marks

Musculoskeletal - tall, along arm spam, long digits, scoliosis, hypermobility and more

70
Q

What is the Ghent criteria

A

Used to diagnose Marfan syndrome in absence of family history

71
Q

What are the cores for the Ghent criteria to diagnose Marfan syndrome

A

Aortic root Z-score ≥ 2 AND ectopia lentis

Aortic root Z-score ≥ 2 AND FBN1 mutation

Aortic root Z-score ≥ 2 AND systemic score ≥ 7

Ectopia lentis AND FBN1 mutation associated with aortic aneurysm

72
Q

What is used to diagnose Marfan syndrome when there is a family history

A

Either of the following
Ectopia lentis
Systemic score ≥ 7
Aortic root Z-score ≥ 2

73
Q

What is the aortic Z-score

A

Statistical term to normalise the aortic size to the standard for a person of that age and size

This is because aortic diameter varies depending on various factors

Aortic score >2 meaning above 2 SD from the normal

74
Q

What are the cardiovascular features of Marfan

A

Most common cause of morbidity/mortality (~80%)

Aortic root disease > aneurysms, AR, dissection
50% of children, 80% of adults
May lead to neurovascular complications

Mitral valve prolapse (minor criterion
Most common valve defect 60-80%
Worsens with time, complicated by rupture

Arrhythmias

75
Q

What is the progression of Marfan syndrome

A

Prognosis can be poor if diagnosed in infancy/childhood

Severe Marfan can include deforming skeletal anomalies

• Later-onset symptoms:
	○ Cataracts, retinal detachment, easy bruising (but normal wound healing), stretching of the spinal dura with neck/abdominal pain, osteoporosis, risks in pregnancy (e.g. vascular)
76
Q

What are the early manifestations/symptoms of Marfan syndrome

A

Early manifestations:
Heart: abnormal echo (96%), aortic root enlargement (84%), mitral valve prolapse (58%)

Eyes: ectopia lentis (70%), myopia (60%)

Skeletal: pectus deformities (68%), scoliosis (44%), flat feet (44%)

Height >95th centile (56%), arachnodactyly (88%), striae (24%)

77
Q

What are the later-onset manifestations/symptoms of Marfan syndrome

A

Cataracts, retinal detachment, easy bruising (but normal wound healing), stretching of the spinal dura with neck/abdominal pain, osteoporosis, risks in pregnancy (e.g. vascular)

78
Q

What is the screening options for Marfan syndrome

A

At least annual evaluation
Clinical history
Examination
Echocardiography

Consider aortic root surgery when the aortic diameter at the sinus of Valsalva exceeds 5 cm

Enhanced monitoring in pregnancy (risk of aortic dissection if the aortic diameter exceeds 4 cm)

79
Q

What is pharmacotherapy

A

Beta blockade
Calcium channel blockers
ARB’s (Angiotensin II receptor blockers)

80
Q

What is Loeys Dietz syndrome

A

Autosomal dominant inherited connective tissue disorder

81
Q

What genes are involved in Loeys Dietz syndrome

A

TGFBR1~20%-25%, TGFBR2~55%-60%, SMAD3~5%-10%, TGFB2~5%-10%5.TGFB3~1%-5%, SMAD2~1%-5%

Differential diagnosis to Marfan - rarer, exact prevalence unknown and ocular features absent

82
Q

What are the cardiovascular symptoms of Loeys Dietz syndrome

A

Cardiovascular - arterial tortuosity, congenital heart defects (ASD, PDS, BaV)
• Eyes, Head and Neck
○ Widely-spaced eyes (hypertelorism), blue-gray sclerae, wide or split uvula, cleft palate, cervical spine instability or malformation

Skin - easy bruising, wide scars, soft skin texture, translucent skin

Bones - club foot (talipes equinovarus), osteoporosis

Gastrointestinal problems - malabsorption, diarrhoea, abdominal pain, bleeding, inflammation, other

Other - allergies (food/environmental), spleen/bowel rupture, uterine rupture during pregnancy

83
Q

What is one cardiac symptom different in Loeys Dietz syndrome vs Marfan

A

Aortic dissection occurs at smaller diameters than in Marfan

Vascular disease not limited to the aortic root, requires MRI scan to look at other vessels

84
Q

What are the treatments of Loeys Dietz syndrome

A

Beta-adrenergic blockers or other medications are used to reduce hemodynamic stress

Aneurysms are amenable to early and aggressive surgical intervention

Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage

Standard treatment for club feet and severe pes planus

Craniofacial management for cleft palate and craniosynostosis

85
Q

What are collagenopathies

A

Genetic conditions which affect the collagen genes

Includes Ehlers-Danlos syndrome and other connective tissue disorders

86
Q

What is thoracic aortic aneurysm disease (TAAD)

A

Can be syndromic or non-syndromic

There is a wide range of genes - some involved can overlap with those seen in syndromic diseases

TGFBR1/2, MYH11, FBN1, SMAD3, MYLK, ACTA2

87
Q

What are the classifications of genes associated with TAAD

A

Muscle contraction - problems = more prone to be stretched, causing aneurysm

ECM - provide structural support = more prone to being stretched

TGFB - interacts with some of the ECM, and affects activation of transcription

Clinical Applications of Genomics in Rare Disease and Cancer (10 decks)

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