Clin Med - Clin Genetics Flashcards
What are the types of genetic diseases?
- Mendelian disorders (inherited)
- Chromosomal disorders (not inherited)
- Multi-factorial diseases and genetic susceptibility
- Hereditary cancer syndromes
Mendelian Disorders
- Classical or “simple” genetics
- Follows Gregor Mendel’s laws of inheritance
- Single gene mutation
Achondroplasia
Most common cause of disproportionate short stature (1/27,000 prevalence at birth)
What is the inheritance pattern of achondroplasia?
Autosomal dominant inheritance (50% risk to offspring)
What is affected by achondroplasia?
Increased inhibition of cartilage cell growth, leads to shortening of limbs
What is Alpha-1 Antitrypsin?
- Serine protease inhibitor
- Protects connective tissue of lungs from elastase released by leukocytes
Alpha-1 Antitrypsin Deficiency
Predisposition to emphysema and cirrhosis
Alpha-1 Antitrypsin Deficiency Inheritance pattern
Autosomal Recessive Inheritance
Autosomal Dominant Polycystic Kidney Disease can cause…
- Age-dependent cysts (kidney, liver, pancreas, spleen)
- Cardiovascular abnormalities (HT, MVP, brain aneurysms, LVH)
- Connective tissue abnormalities (hernia, diverticuli)
Autosomal dominant polycystic kidney disease affects which group of people?
All ethnic groups.
Charcot-Marie-Tooth Disease
- Group of hereditary motor and sensory neuropathies
- Most common inherited neuromuscular disorder (1/2500 prevalence)
Charcot-Marie-Tooth Disease inheritance pattern
Autosomal dominant or recessive
Charcot-Marie-Tooth Disease Clinical Presentation
Presents between 5-15 yoa, typically with
foot drop
-very slow progression
Cystic Fibrosis
Most common life-limiting AUTOSOMAL RECESSIVE disorder in Caucasians (1/3300 births)
Cystic Fibrosis Characteristics
- Presents with symptoms in childhood
- Causes obstructive lung disease
Chronic Sinopulmonary features of CF
- Chronic cough
- Copious thick sputum
- Persistent colonization with bacteria
- Airway Obstruction
- Nasal polyps
Male urogenital abnormalities with CF
absence of vas deferens - infertility
GI abnormalities with CF
- Meconium ileus
- Rectal prolapse
- Intestinal Obstruction
- Failure to thrive
- Pancreatic insufficiency - steatorrhea
- Pancreatitis
Salt Loss Syndrome with CF
- Acute salt depletion
- Chronic Metabolic Acidosis
CF Diagnosis Requires 1 Criterion From Each Group
Group 1
- One or More Clinical Features
- Sibling with CF
- Positive Neonatal IRT (immunoreactive trypsinogen test)
Group 2 -Abnormal SWEAT CHLORIDE >60mM on two occasions -Identification of two CFTR mutations -Abnormal NASAL POTENTIAL DIFFERENCE
CF Treatment - Medications
- Anti-inflammatory medications
- Bronchodilators
- Nebulized hypertonic saline
CF Treatment - Supplements
- Pancreatic enzymes
- Vitamin D and calcium
CF Treatment - Physical Therapy
- Chest Physiotherapy
- Mechanical Vest
CF Treatment - Preventative
- Prophylactic antibiotics
- Vaccinations
CF Complications
- Pneumonia
- Pneumothorax
- Infertility
- Meconium ileus or distal intestinal obstructive syndrome
CF Prognosis
Median survival 40yrs
Duchenne Muscular Dystrophy inheritance pattern
X-linked recessive
Duchenne MD Characteristics
- Loss of ambulation between 7-13 years of age, wheelchair
- Mutation on DMD gene on Xp21 –> defective dystrophin protein = loss of proteins in muscle cell membranes
Duchenne MD Clinical Features
- Delay of motor milestones
- Gait disturbance and calf hypertrophy
- Proximal Limb Weakness:
- -Difficulty rising from floor or climbing stairs
- -Gower’s Maneuver: child will push up on his thighs with his hands to get up off the floor
- -Unable to jump with both feet together
- Speech delay, 30% have learning disability
MD Diagnosis
- Elevated creatinine phosphokinase (CPK) >10x normal (Essentially a screening, then test further)
- DNA testing for mutation
- Muscle biopsy – helpful if genetic tests are negative, provides prognostic info
MD Life Expectancy
Common until the 30s now.
MD Treatment
- Refer for genetic counseling
- Gene therapy in the future, hopefully
- Corticosteroid Therapy
- Assistive Devices for mobility
- Treat/prevent contractures
- Bracing or surgery for scoliosis
- Physical therapy
- Ventilation support
- Monitor for cardiomyopathy
Ehlers-Danlos Syndrome (EDS) is a mutation of…
defective proteins, collagens
EDS inheritance pattern
Usually autosomal dominant (some are AR)
EDS types (3)
SKIN: skin fragility, abnormal scarring, elasticity
JOINTS: musculoskeletal discomfort, susceptibility to OA, hypermobility
VESSELS: fragility, prone to arterial rupture, easy bruising, higher mortality
Which EDS type is the most common?
Hypermobility
Which EDS type is rare, but the most serious?
Vascular
EDS clinical features (many)
- Hypermobile joints, High Beighton Score
- Pes planus, genu valgum, scoliosis
- History of dislocations??
- Soft, velvety skin that is highly elastic and fragile
- Easy bruising
- ‘Cigarette paper’ scars, abnormally wide/thin surgical scars
- Early onset arthritis
- Floppy mitral valve - causes heart murmur
- Recurrent or multiple abdominal hernias
EDS Monitoring
During pregnancy, high risk for:
- preterm delivery
- hemorrhage
- wound complications
- uterine rupture
- Monitor all for aortic dilation
EDS Preventative Measures
- Avoid trauma and contact sports, avoid high impact exercise
- Maintain healthy weight
- Refer for genetic counseling!
Hereditary Hemochromatosis inheritance pattern
Autosomal Recessive disorder of iron absorption
What population is affected by hereditary hemochromatosis?
1% of Irish
What causes hereditary hemochromatosis?
dysfunction of HFE protein –> decreases HEPCIDIN production, so hepcidin can’t down regulate absorption
Why does hereditary hemochromatosis cause iron overload?
Excessive intestinal absorption + limited means to excrete = iron overload
Why does hereditary hemochromatosis present in early adulthood?
Progressive iron overload will take years to present clinically.
Hereditary hemochromatosis clinical features
- Bronzed skin pigmentation
- Erectile dysfunction, decreased libido
- Diabetes
- Fatigue, weakness
- Joint pain/Hand arthritis
- Elevated LFTs
Hereditary hemochromatosis diagnosis
-LABS: Elevated serum ferritin (>200 women, >250 men), elevated serum iron, elevated transferrin saturation
-Genetic testing for mutations
+/- Liver Biopsy (for prognosis)
Hereditary hemochromatosis treatment
- Serial Phlebotomy weekly or biweekly (Maintain ferritin between 50-100ng/mL)
- Limit alcohol consumption
- If cirrhosis present, screen for HCC with ultrasound every 6 months
- Refer to hematologist and gastroenterologist, possible genetic counseling
Huntington Disease
Progressive neurodegenerative disorder
Huntington disease inheritance pattern
Autosomal dominant
Huntington disease Triad
1. Involuntary movements: Chorea = irregular migrating contractions Athetosis = twisting, writhing 2. Psychiatric disturbance 3. Dementia
Huntington disease age of onset
35-40 yoa
*Death within 15 years of symptom onset
Huntington disease clinical features (movements)
Abnormal Movements:
- Facial grimacing
- Chorea, jerks, pseudo-tics
- Puppet-like gait
- Motor impersistence = Inability to sustain a motor act e.g. protruding the tongue or grasping
- Oculomotor apraxia = Inability to intentionally move the eyes quickly w/o blinking or head thrusting
- Swallowing impairment
Huntington disease clinical features (psych)
- Personality change
- Poor self-control, irritability
- Depression
- Socially withdrawn
- Cognitive impairment
- Dementia
Huntington Disease Diagnosis
Family history, exam, confirm with genetic testing, consider neuroimaging
Huntington Disease Management
- Refer for genetic counseling
- Refer family to support group
- Support, end of life care discussion
- Anti-psychotics to suppress chorea, agitation
- Institutionalization
Long QT Syndrome
- Prolonged ventricular repolarization
- predisposes to arrhythmias
- syncope
Long QT Syndrome Inheritance Pattern
Autosomal dominant
What is mutated in long QT syndrome?
genes that code for potassium or sodium channels
Long QT Syndrome Clinical Features
- Onset pre-teen or teenage years
- Sx: syncope during physical activity or emotional upset, WITHOUT warning
- Triggers can be gene specific:
- -Running, swimming (LQT1)
- -Startle (LQT2)
- -Anger, crying, stress
Long QT Syndrome Diagnosis
History, family history (fainting, “epilepsy”, sudden death), EKG, genetic testing
Long QT Syndrome Treatment
- Lifestyle Modification: approach intense physical activity, roller coasters, scary movies with caution
- Avoid drugs that cause QT prolongation
- Beta-blockers
- Implanted defibrillator
- Refer to cardiologist and genetic counselor
Marfan Syndrome mutations cause
Disorder of connective tissue
What is the main cause of morbidity/mortality in Marfan syndrome?
Cardio complications
Marfan Syndrome inheritance pattern
Autosomal dominant
Cardio clinical features of Marfan Syndrome
- Aortic root dilation, dissection, aneurysm
- Mitral valve disease
Musculoskeletal clinical features of Marfan Syndrome
- Arachnodactyly
- Arm span > height
- Scoliosis, chest wall deformity,
- Joint hypermobility, Joint dislocation
Pulmonary clinical features of Marfan Syndrome
Recurrent spontaneous pneumothorax
Cystic lung disease
Ocular clinical features of Marfan Syndrome
- Dislocation of ocular lens
- Myopia, visual acuity problems
- Retinal detachment
Skin clinical features of Marfan Syndrome
- Abnormal scarring
- Hyperextensibility
- Recurrent hernias
- Skin translucency, striae
Mouth clinical features of Marfan Syndrome
- Dental Crowding
- High arched palate
What 2 signs are used for evaluation of Marfan Syndrome?
- Steinberg sign - fold thumb into closed fist. The test is positive if thumb tip extends from palm.
- Walker-Murdoch sign - grip your wrist with opposite hand, if thumb and pinky overlap the test is positive.
Marfan Syndrome Diagnosis
- Family history
- Physical exam findings, measurement, Breighton score increased
- Genetic testing
- Echocardiogram
- Slit-lamp examination of eyes
- X-rays
- MRI of L-spine
Diagnosis can be uncertain in partial cases
Treatment/Management of Marfan Syndrome
- Focused on prevention of complications
- Beta-blockers
- Elective aortic repair, valve repair
- Treat scoliosis
- Pleurodesis prn
- Eye surgery prn
- Annual echocardiogram
- Referral to cardiology and ophthalmologist
- Genetic counseling
- Avoidance of contact sports
Neurofibromatosis (Type 1)
AKA “von Recklinghausen disease”
What causes neurofibromatosis type 1?
Defective protein neurofibromin
Cardinal features of Neurofibromatosis type 1
Café-au-lait spots
Neurofibromata
Lisch nodule in the iris
Clinical features of Neurofibromatosis type 1
SKIN: Café-au-lait spots, freckling, lumps/bumps, tumors appear late childhood
NEURO: seizures, learning difficulties, neuromotor problems, aneurysms
BONE: scoliosis, bone cysts, thinning of long bone cortex –> tibial bowing
EYES: optic gliomas, Lisch nodule (iris hamartomas), absence of greater wing of sphenoid bone –> pulsating exophthalmos
Neurofibromatosis type 1 treatment/management
- No specific treatment available
- Surgery to correct deformity
- Irradiation of tumors
- Optic gliomas/CNS lesions treated with radiation or chemotherapy
- Refer for genetic counseling
Osteogenesis Imperfecta is commonly called
“brittle bone disease”
Osteogenesis imperfecta inheritance
autosomal dominant or recessive
What is mutated in osteogenesis imperfecta?
defective protein procollagen (component of bone, ligaments, and tendons) –> defective collagen
Osteogenesis imperfecta clinical features
- Diagnosed at birth
- Weakened bones
- Shortened height and stature
- Blue sclera
- Hearing loss
- Joint hypermobility and flat feet
- Poor dental development
Which type of osteogenesis imperfecta is lethal?
“type II is gonna kill your ass at birth”
What is the most mild form of osteogenesis imperfecta?
type I - blue sclera, hypermobility, +/- fractures
Severity of 4 types of osteogenesis imperfecta
Type I- mild, no deformity
Type II- perinatal lethal
Type III- severely deforming
Type IV- moderately deforming
Diagnosis of osteogenesis imperfecta
- Suspect in children with recurrent fractures or blue sclera
- Abuse should be in differential
- Genetic testing
- Lab analysis of type 1 procollagen from skin biopsy
- Chorionic villus sampling
- Prenatal ultrasound can detect severe forms
Osteogenesis imperfecta treatment
- Growth hormone
- Bisphosphonates (same as osteoporosis treatment)
- Physical Therapy, Occupational Therapy
- Bracing, assistive devices
- Referral to orthopedic surgeon
- Cochlear implant for hearing loss prn
- Refer to genetic counseling
Retinitis Pigmentosa is
Slowly progressive degeneration of the retina
*Most common inherited retinal dystrophy
Retinitis Pigmentosa inheritance pattern
can be AD, AR, or XLR
Mutation causing retinitis pigmentosa
Leads to defective retinal proteins
Retinitis Pigmentosa clinical features
- Impaired night vision (early), eventually lost
- Progressive loss of visual field
- Loss of central vision (later)
- Myopia
- Family history of RP or adult onset blindness
- Abnormal fundoscopic exam
- -Hyperpigmentation of retina
- -Narrowing of retinal arterioles
- -Macular edema
- -Waxy yellow appearance of disk
Retinitis Pigmentosa treatment/management
- No way to reverse damage
- Refer to ophthalmologist
- Refer for genetic counseling
- Supplements that slow progression:
- -Vitamin A palmitate
- -Omega-3 fatty acids
- -Lutein plus zeaxanthin
- FUTURE: Intraocular computer chip implants (Cyborg???)
Non-Mendelian Genetic Syndromes are due to…
chromosomal disorders in egg or sperm, present prior to fertilization
What is the most common cause of intellectual disability?
Chromosomal disorders
Common chromosomal syndromes (3)
Trisomy 21 or Down Syndrome
Trisomy 18 or Evans Syndrome
Monosomy X or Turner Syndrome
What tests are done to evaluate chromosomal disorders?
- Karyotyping
- Microarray
- FISH (fluorescence in situ hybridization)
Define polygenic
Cumulative affect from several genetic loci
Multi-Factorial Disorders/Complex Inheritance
GENETIC SUSCEPTIBILITY + ENVIRONMENTAL FACTORS/LIFESTYLE
What are the 2 types of complex characters?
- Continuous Characters = we ALL have them, but differing degree (height, weight, BP, behavior)
- Discontinuous Characters = some people have them, but most do NOT, family clusters
(cleft palate, congenital heart disease, hip dysplasia, neural tube defects, schizophrenia, type 1 diabetes
Hallmarks of complex disease
- Clustering of disease in multiple family members
- NO predictable inheritance pattern
- Later age at onset of disease
- Variable expression –> difficult to predict who will develop symptoms, which symptoms, and severity of symptoms
List the multifactorial diseases
Diabetes Polygenic Hyperlipidemia Monogenic Lipoprotein Disorders -Familial Hypercholesterolemia -Familial Defective apoB-100 -Autosomal Recessive Hypercholesterolemia Hypertrigliceridemia
Characteristics of type 2 diabetes
> 60 genes are associated with an increased risk of Type 2 Diabetes
40-60% heritability, most polygenic
- Rare monogenic forms
- Twin studies: 60% higher rate of diabetes if monozygotic twin has it
- Environmental factors: obesity, sedentary lifestyle
Polygenic Hyperlipidemia
- May present with premature symptomatic atherosclerotic disease
- Often a family history of high cholesterol and/or premature CV disease
- Look for xanthomas
Familial Hypercholesterolemia inheritance pattern
Autosomal dominant
Familial Hypercholesterolemia characteristics
- Onset at birth
- can have MI at 35-40 due to strikingly elevated LDL-C
- xanthomata
Familial Defective apoB-100
- defective LDL receptor leads to poor binding –> diminished clearance of LDL
- less xanthomata than familial hypercholesterolemia
Familial Defective apoB-100 inheritance pattern
autosomal dominant
Autosomal Recessive Hypercholesterolemia
- Mutation of the ARH gene that encodes for protein involved with LDLR
- Later onset of CAD
Hypertriglyceridemia Characteristics
-Multiple gene loci + environmental factors (alcohol, obesity, etc)
-Usually a family history of high triglycerides
Types of primary hypertriglyceridemia, familial hypertriglyceridemia, familial combined hypertriglyceridemia, LPL deficiency, apolipoprotein C-II
-Secondary causes: diabetes, alcohol, obesity, hypothyroidism, medications
Hypertriglyceridemia clinical features
xanthoma
lipemia retinalis
pancreatitis
List the Hereditary Cancer Syndromes (3)
- Hereditary Breast and Ovarian Cancer Syndrome (BRCA 1 and BRCA 2)
- Familial Adenomatous Polyposis
- Multiple Endocrine Neoplasia
Genetic testing for hereditary cancer syndromes - who?
- Cancer at young age (<40-50)
- Multiple cancers in single individual
- Bilateral cancer in paired organs (kidney, breast)
- Multiple relatives with same cancer
- Unusual cases of specific cancer type (breast CA in man)
- Congenital anomalies or precursor lesions associated with cancer syndromes
- Certain racial/ethnic groups
Genetic testing for hereditary cancer syndromes - what?
Looks for mutations in chromosomes, genes, or proteins
CANCER: check for mutation, confirm if inherited
NO CANCER: family history, check for mutation to assess risk
Genetic testing for hereditary cancer syndromes - how?
- Blood, saliva, cells from cheek swab, skin cells, amniotic fluid
- Tumor cells
- Ordered by medical provider or genetic counselor
Identify patients at risk for genetic disease
- advanced maternal age >35
- consanguinity
- previous h/o a child with birth defects or genetic disorder
- personal or fam hx suggestive of genetic disorder
- high-risk ethnic groups
- documented genetic alteration in a family member
- ultrasound or prenatal testing suggestive a genetic disorder
What is the purpose of genetic screening?
determine the risk of a group of patients who belongs to a certain age group or ethnic group, population-based, large number of people screened
What is the purpose of genetic testing?
- determines status of a specific individual, performed on patients already at high risk for a disease/condition due to a positive screen or family history or ethnic background
- tests for a specific disease-causing gene
