A defect in which gene causes cystic fibrosis?
CFTR (Cystic Fibrosis Transmembrane Regulator)
What is the most common CFTR mutation?
ΔF508
What does the CFTR transporter control?
Controls chloride transport across epithelial membranes (mucous, sweat, saliva, tears and digestive enzymes)
Which 9 conditions are screened in newborn screening?
- Cystic fibrosis
- Sickle cell
- Congenital hypothyroidism
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- Maple syrup urine disease (MSUD)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type I (GAI)
- Homocystinuria (Pyridoxine unresponsive) (HCU)
What are some symptoms of cystic fibrosis?
- Meconium ileus
- FTT (failure to thrive)
- Sinusitis
- Recurrent LRTIs
- Greasy/bulky stools
Prolapse
Other than newborn heel prick test, how would you screen for cystic fibrosis?
Sweat test CF kids are salty - Pilocarpine and current - Collect sweat - Measure chloride content - Can be confirmed with gene testing
What are some treatments for cystic fibrosis?
- Antibiotics +++ inhaled, oral and IV
- Pulmonary Rehab – Physio, airway clearance techniques
- The Vest
- DNAse
- Transplant
- High calorie diet
- Creon - amylase, lipase and protease
- ADEK vitamins
- Kalydeco or kaftrio
What are some external features of Trisomy 21?
- Hypotonia
- Upward slanting palpebral fissures
- Brachycephaly - flat occiput
- Clinodactly with short 5th finger
- Protruding tongue
- Flat nasal bridge
- Epicanthal folds
- Brushfield spots (spots on iris)
- Ear abnormalities (low set ears, stenotic meatus)
- Single palmar crease
- Loose nuccal skin
- Short fingers
- Sandal gap
What are some internal features of Trisomy 21?
- AVSD, VSD, ASD
- Hirschprung’s disease - lack of nerves in rectum
- Duodenal atresia, trachea-oesophageal fistula
- Low IQ (mean 50)
- ENT issues
- Hypothyroidism
- Atlanto-axial instability
- Cataracts
- Transient abnormal myelopoiesis –> Acute Myeloid Lymphoma
What genetic abnormality is Edward’s syndrome?
Trisomy 18
What are some features of Edward’s syndrome?
- Clenched hand, with overlap of the 2nd and 5th fingers, over the 3rd and 4th
- Rocker bottom feet
- Micrognathia, prominent occiput, micro-ophthalmia
- Low set ears
- VSD/ASD
- Generalised muscle spasticity
- Renal abnormalities
- Mental retardation
What genetic abnormality is Patau’s syndrome?
Trisomy 13
What are some features of Patau’s syndrome?
- Holoprosencephaly
- Polydactyly
- Seizures
- Deafness
- Microcephaly
- Midline cleft lip/palate
- Abnormal ears
- Sloping forehead
- Cutis aplasia
- Omphalocele
- Cardiac and renal anomalies
What genetic abnormality is Turner’s syndrome?
45 X0
What are some features of Turners syndrome?
- Low birth weight and length
- Short stature
- Low posterior hairline
- Webbed neck
- Puffy hands and feet (due to lymphedema)
- Shield chest and wide spaced nipples
- Cubitus valgus - elbows turned inward with forearms deviated outwards
- high palate
- low set ears
What is the genetic abnormality in Klinefelter’s syndrome?
47, XXY
What are some features of Klinefelter’s syndrome?
- 1 in 600 male births
- Usually presents in adolescence
- Muscle weakness
- Increased height
- Poor coordination
- Reduced body hair
- Gynaecomastia
- Reduced libido
- Primary hypogonadism
- Low testosterone
- High FSH
- Microorchidism
- Infertility
What is the genetic abnormality in Williams syndrome?
7Q11.23 deletion
What are some features in Williams syndrome?
- 1/1000 births
- Elastin region
- IQ differences
- Characteristic “elfin” facies:
- Short nose, broad nasal tip
- Small widely spaced teeth
- Small chin
- Wide mouth
- Puffy eyes
- Full cheeks
- Full lips
- Can appear more gaunt as adult
- Supravalvular aortic stenosis
- Hypercalcaemia
- Diabetes
- Hypothyroidism
- Visuo-spatial and numerical difficulties
- Spoken language and music abilities
- Cocktail party chatter/personality
- overfriendliness
- lack of fear with stranger
- strong pro-social compulsion
- excessive talkativeness
- verbal fluency with extensive and expressive speech rich in vocabulary
What is the genetic abnormality in Prader-Willi syndrome?
Deletion of paternal 15Q11-Q13
What are some features of Prader-Willi syndrome?
- Characteristic facies
- Distinctive evolution of condition
- Impaired hypothalamic function
Early features:
- Hypotonia
- Failure to thrive
- Poorly developed genitals
- Developmental delay (walking 24m, enhanced VP skills)
- Hyperphagia
- Tantrums –> psychosis
Later features:
- Central obesity
- IHD
- Type 2 DM
- OSA
- Short stature
- Hypogonadism: incomplete, delayed or abnormal pubertal development. Men are thought to be infertile
- Intellectual disability
What is the threshold model?
- Some polygenic diseases do not show a normal distribution but instead are either present or absent (mimicking a single gene disorder)
- These traits show a liability distribution:
- Those with few disease associated alleles or limited exposure to environmental factors have a limited chance of developing the disease
- Those with more disease associated alleles or more exposure to environmental factors have an increased chance of developing the disease
What is epistasis?
- ‘Gene-gene interactions’
- Combined variant effects qualitatively or quantitatively different from single effects
What is pleiotropy?
- Single gene/variant causative of different traits
- Affected traits not always obviously related
- Antagonistics pleiotropy
