Adult General Genetics Flashcards
What is a primary cause of death
Sudden cardiac arrest
What are some structural cardiac abnormalities
Hypertrophic, arrhythmogenic, congenital (inc. Marfan), mitral valve prolapse/aortic stenosis
What are some electrical cardiac abnormalities
Wolff Parkinson White syndrome, congenital long QT (incl. Brugada syndrome), catecholaminergic polymorphic ventricular tachycardia (CPVT)
What are some acquired cardiac abnormalities
Infection (myocarditis), trauma (commotio cardis), toxicity (drugs), environment (hypo/hyperthermia)
What are 3 examples of cardiac disease types
Congenital heart disease
Cardiac muscle disease
Cardiac rhythm disturbance
What are some examples of cardiac abnormalities
Cardiac anatomy abnormalities - congenital heart disease, valvular heart problem, aortopathies
Cardiac blood supply abnormalities - coronary heart disease
Cardiac conduction abnormalities
Where should the heart be located
To the left
What are common causes of congenital heart disease
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)
What are ciliopathies
Group of conditions with a wide number of abnormalities
Ahlstrom syndrome - lead to dilated cardiomyopathy
How is the foetal circulation different to the postnatal circulation
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
What happens to the ductus venosus and arteriosis postnatally
The ductus venosus and arteriosus are artefacts post-natally
Closure of the ductus arteriosus becomes the ligamentum arteriosum by a decrease in prostaglandin
What are the three types of cardiomyopathy
Hypertrophic
Dilated
Arrhythmogenic
What is hypertrophic cardiac myopathy
Hypertrophic - thickening of the ventricular walls
Involves mutations in sarcomeric proteins
What is dilated cardiac myopathy
Dilated - most common cause for heart transplant, heart muscle fails, more non-genetic causes
Involves mutations in cytoskeletal proteins /sarcomeric
What is arrhythmogenic cardiac myopathy
Arrhythmogenic - aka arrhythmogenic right ventricular cardiomyopathy, but it affects both ventricles
Involves mutations in desmosomal proteins
What is used to detect the difference between cardiomyopathies
NGS panels as they are multigenic with overlap between phenotypes
Describe the two types of hypertrophic cardiomyopathy
Apical and septal, where apical is less likely to be due to genetic causes
What is the clinical presentation of hypertrophic cardiomyopathy
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
What can be seen on an ECG when looking for hypertrophic cardiomyopathy
Septal hypertrophy - tall R waves and abnormal Q wave
Apical hypertrophy - T wave inversion
Multifactorial - associated with diabetes, underlying cardiac diseases
What genes are involved in hypertrophic cardiomyopathy
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
What percentage of dilated cardiomyopathy is genetic
30-40%
What are some causes of dilated cardiomyopathy
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
What is the clinical presentation of dilated cardiomyopathies
Shortness of breath, cough, swelling of ankles, syncope, fatigue, arrhythmias
What genes are involved in dilated cardiomyopathy
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
What are the characteristics of arrhythmogenic cardiomyopathy
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
What genes are involved in arrhythmogenic cardiomyopathy
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
What can treat arrhythmogenic cardiomyopathy
Implantable devices (pacemaker) treats rhythm while implantable defibrillator protects and only acts when needed
What are some cardiomyopathy genes and their inheritance patterns
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
What are channelopathies are the three types
Primary rhythm disturbances
Long QT
Brugada Syndrome
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
What is Q-T interval
Q = when the heart is full while T = when the heart contracts/empties
What are the three types of long QT syndrome
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
What is Brugada syndrome
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)
What is CPVT
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
What are some neurogenetic disorders and diseases
Obvious ones - epilepsies, neurodegenerative disease, movement disorders, neurofibromatoses
Less obvious - mitochondrial disease, channelopathies,
Diseases - Charcot-Marie Tooth Disease, Muscular Dystrophies, ALS/MND
Why is making a diagnosis important
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
How can you make diagnoses
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
If a baby is born with joint problems, reduced movement and the mother has difficulties in loosening grip what can be the cause
Myotonic dystrophy
What are the two types of myotonic dystrophy
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
What are the major effects of myotonic dystrophy type 1
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
What symptoms may a neonate with congenital myotonic dystrophy have
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
What is the pathophysiology of myotonic dystrophy
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
What is the molecular diagnosis of myotonic dystrophy
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
What is anticipation (triplet repeat)
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
Is the triple expansion repeat instability of myotonic dystrophy influenced more maternally or paternally
Maternally
Is the triple expansion repeat instability of Huntington’s disease influenced more maternally or paternally
Paternally
What us Huntington’s disease
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
What is spinal muscular atrophy caused by
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
What is the genetic risk of Alzheimer disease
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)
What are the symptoms of Alzheimers disease
Slowly progressive memory difficulties
Confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations
Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism
How can you diagnose Alzheimer’s disease
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
What are the causes of early onset familial Alzheimer’s disease
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
What is a key Alzheimer’s disease genetic risk factor
ApoE
What does the apoE gene do
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
What are the apoE variants
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.
What is the risk variants associated with ApoE
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
How significant are the apoE risk variants
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
Why is finding risk variants important
Insight into pathogenic mechanisms
Druggable targets
Risk stratification in clinical trials
There is limited clinical utility in the context of the individual patient
What is the aorta, describe its pathing
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
What are the three aortopathies categories (not diseases/syndromes)
Aortic aneurysm
Aortic dissection
Aortic regurgitation
What is an aortic aneurysm
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
What is an aortic dissection
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
What is an aortic regurgitation
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
What are examples of aortopathy diseases/syndromes
Marfan syndrome
Loeys-Dietz syndrome
Collagenopathies
Non-syndromic thoracic aortic aneurysm - harder to identify as there are no obvious external features
What type of disorder is Marfan syndrome
Connective tissue disorder
How do males and females vary with Marfan syndrome
Incidence is same
Men have shorter life expectancy
What is the inheritance pattern of Marfan syndrome
AD, with variable expressivity
What is the common gene involved in Marfan syndrome
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
What are the features of marfan syndrome
Long limbs/fingers, downslant eyes, flattened cheek bones, lower jaw pushed back, deep set eyes
What symptoms and systems are affected by Marfan syndrome
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
What is the Ghent criteria
Used to diagnose Marfan syndrome in absence of family history
What are the cores for the Ghent criteria to diagnose Marfan syndrome
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
What is used to diagnose Marfan syndrome when there is a family history
Either of the following
Ectopia lentis
Systemic score ≥ 7
Aortic root Z-score ≥ 2
What is the aortic Z-score
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
What are the cardiovascular features of Marfan
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
What is the progression of Marfan syndrome
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)
What are the early manifestations/symptoms of Marfan syndrome
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%)
What are the later-onset manifestations/symptoms of Marfan syndrome
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)
What is the screening options for Marfan syndrome
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)
What is pharmacotherapy
Beta blockade
Calcium channel blockers
ARB’s (Angiotensin II receptor blockers)
What is Loeys Dietz syndrome
Autosomal dominant inherited connective tissue disorder
What genes are involved in Loeys Dietz syndrome
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
What are the cardiovascular symptoms of Loeys Dietz syndrome
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
What is one cardiac symptom different in Loeys Dietz syndrome vs Marfan
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
What are the treatments of Loeys Dietz syndrome
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
What are collagenopathies
Genetic conditions which affect the collagen genes
Includes Ehlers-Danlos syndrome and other connective tissue disorders
What is thoracic aortic aneurysm disease (TAAD)
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
What are the classifications of genes associated with TAAD
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
