Genetics Flashcards
- 46 chromosomes
- 22 matching pairs with matching genes (autosomes)
- 1 pair of sex chromosomes (may match XX, or differ XY)
Changes in the number of chromosomes can cause genetic disease. Give examples:
- Down’s syndrome - an extra chromosome 21
- Sex chromosome duplication or deletion - Turner’s XO, Klinefelter’s (XXY or XXYY).
Gross structural changes in chromosomes can lead to genetic disease. What is translocation?
part of one chromosome is translocated onto another.
If it is a balanced translocation, no genetic info is lost- no clinical effect.
6% of children with Down’s have a translocation rather than trisomy 21.
Gross structural changes in chromosomes can lead to genetic disease. What is deletion? Give an example.
loss of a portion of a chromosome.
* cri-du-chat syndrome - deletion of short arm of chromosome 5.
Single gene abnormalities can be inherited via autosomal dominant inheritance. What is autosomal dominant inheritance? What are the features? Give examples:
- Heterozygotes have the disease (Aa)
- 50% of pregnancies of an affected individual are affected.
- Usually equally affects males and females
- the expression of the gene may vary e.g. marfans, neurofibromatosis, tuberous sclerosis, myotonic dystrophy.
- others: achondroplasia, PKD, Ehlers Danlos, FAP, Huntington’s disease, hyperlipidaemia type II, hereditary non-polyposis colorectal carcinoma, heretitary haemorrhagic telangiectasia, peutz-jeghers, retinoblastoma, von hippel-lindau, osteogenesis imperfecta, alpha-1 anti-trypsin deficiency.
Single gene abnormalities can be inherited via autosomal recessive inheritance. What is autosomal recessive inheritance? What are the features? Give examples:
- disease only manifests in the homozygote
- therefore the faulty gene must be inherited from both parents
- the risk of an affected (homozygote) pregnancy when both parents are carriers is 1 in 4 (25%)
- risk of having a carrier (heterozygote) child is 50%
- risk of having a genotypical child is 25%.
- Usually equal males and females
- Affected individuals will have unaffected children unless their partner is a heterozygote. An affected parent, with a genotypical partner - all the children will be carriers.
- e.g sickle cell disease, thalassaemias, CF, albinism, ataxic telangiectasia, CAH, cystinuria, glycogen storage disease, haemochromatosis, homocystinuria, Lipid storage disease: tay-sachs, gaucher, niemann-pick, PKU, wilson’s disease.
- Autosomal dominant traits generally tend to be less severe than autosomal recessive traits, and conditions which are lethal in early childhood more likely to be autosomal recessive, for example Tay-Sachs disease which is usually fatal by five years of age.
Single gene abnormalities can be inherited via sex-linked inheritance. What is sex-linked inheritance? What are the features? Give examples:
- most are X-linked recessive. Inherited from the mother, and affect MALE offspring.
- A heterozygote mother carrying the X-linked gene: if she has a boy - there is a 50% chance of them having the disease. If she has a girl, there is a 50% chance of them being a carrier
- An affected father, having a child with an unaffected mother with two normal X chromosomes: Sons will be unaffected, daughters will all be carriers.
- e.g. fragile X syndrome, haemophilia, red-green colour blindness, Duchenne’s and Becker muscular dystrophy, G6PD deficiency, androgen insensitivity syndrome, retinitis pigmentosa, nephrogenic diabetes insipidus.
- Female carriers of X-linked disorders sometimes exhibit symptoms of that disorder - if their normal X chromosone is ‘inactivated’ - symptoms are similar/milder.
How do mitochondrial disorders lead to genetic disease? give examples
- mitochondria have their own DNA (mtDNA)
- thousands of mitochondria in each cell
- affect males and females equally
- mutations in mtDNA can only be inherited through an affected female. We inherit mitochondrial DNA from mothers only (via the oocyte). Men cannot pass the mtDNA mutations onto their children in the sperm.
- So the disease is always passed through the female family line
- e.g. Lebers optic atrophy (central scotoma, loss colour vision, rapid blindness age 30), MELAS (stroke like episodes), MERRF (myoclonus epilepsy), Kearns-Sayre (retinitis pigmentosa)
What is karyotyping?
Direct microscopic visualisation of the chromosomes, suitable for detecting very large, or whole chromosome deletions or copies, e.g. Down Syndrome.
What are the symbols for male, female, affected individuals, deceased in a genetic pedigree?
Which genetic condition causing learning disability is associated with increased risk of Hep B carrier status?
- Down’s syndrome
- Due to immunological defect - more likely to become chronic carriers if infected with HepB virus.
Women of which ancestry are at greatest risk of carrying a breast cancer, BRCA1 or BRCA2 gene mutations?
Jewish: 5–10 times more likely to carry the BRCA1 or BRCA2 gene mutations than women in non-Jewish populations.
Which endocrine condition should doctors be vigilant for in Turner’s syndrome?
Hypothyroidism
* one-third of all women with Turner’s syndrome will develop a thyroid disorder.
* Usually it is hypothyroidism, specifically Hashimoto’s thyroiditis.
* It is easily treated with thyroid hormone supplement.
* There is also an increased risk of diabetes mellitus.
Which genotype results in sickle cell trait?
- sickle cell trait results from inheriting:
- one gene for abnormal Hb S
- one gene for normal Hb A
Which genotype results in homozygous sickle cell disease?
- both genes are for the abnormal Hb S
- they are therefore Hb SS
- called sickle cell anaemia
Which genotype results in heterozygous sickle cell disease?
- results from inheriting:
- one gene for Hb S
- one gene for another abnormal variant
Screening for bowel cancer via colonoscopy is recommended from what age in those at risk?
- from age 40 - high risk
- from age 55 - moderate risk
Risk of Down’s Syndrome increases with maternal age, what are the risks from age 20,30,35,40,45?
- 20yrs 1 in 1500
- 30yrs 1 in 800
- 35yrs 1 in 270
- 40yrs 1 in 100
- 45 yrs 1 in 50
remember by starting at risk of around 1/1000 at 30 years then divide denominator by 3 (3x more common) every extra 5 years of age.
What are the 3 genetic causes of Down’s? How common is each?
- trisomy 21- due to nondisjunction 92%
- robertsonian translocation t(14:21) 6%
- mosaicism 2%
What is the incidence of Down’s syndrome?
- 1 in 1000 live births.
What are the clinical features of Down’s syndrome?
face:
* upslanting palpebral fissures
* epicanthic folds
* protruding tongue
* small low-set ears
* flat face.
- flat occiput
- single palmar crease
- hypotonia
- congenital heart defects
- duodenal atresia
- hirschprung’s disease
- learning disability
What are the cardiac complications of Down’s syndrome?
- atroventricular septal defects (endocardial cushion defect)
- VSD
- tetralogy of fallot
- PDA
What are the later complications of Down’s syndrome?
- subfertility
- learning difficulties
- short stature
- repeated resp infections, hearing impairment from glue ear
- ALL
- hypothyroidism
- atlantoaxial instability
- vision: strabismus, cataracts, blepharitis, glaucoma
- Life expectancy reduced, 50% live to >60years
What is the chromosomal disorder causing Turner’s syndrome? What is the incidence?
- 1 in 2000 female births
- Due to only one X chromosome, or a deletion of the short arm of one of the X chromosomes. 45, XO
What are the clinical features of Turner’s syndrome?
- short stature
- shield chest, widely spaced nipples
- webbed neck
- ptosis, nystagmus
- bicuspid aortic valve, coarctation of aorta (15%) - increased risk aortic dilatation and dissection. Regular monitoring.
- primary amenorrhoea - rudimentary/absent ovaries
- cystic hygroma (usually pre-natal diagnosis)
- lymphoedema of feet
- hypothyroidism - increased autoimmune disease (esp, thyroiditis and Crohn’s)
- horseshoe kidney
- normal lifespan
What is the chromosomal abnormality in Klinefelters syndrome? What are the clinical features?
- Polysomy: XXY or XXYY
- Male appearance
- often undetected until infertility in adult life
- gynaecomastia (increased risk breast Ca)
- reduced facial hair, reduced libido
- small, firm testes
- assoc hypothyroidism, DM, asthma
What is the difference between Friedrich’s ataxia and ataxia telangiectasia?
- friedrich’s is the most common inherited ataxia
- trinucleotide repeat
- presents in adolescence
- with gait and limb ataxia, loss of propriocepition, pyramidal weakness, dysarthria. Kyphoscoliosis.
- HOCM occurs in most patients -cause of death
- DM in 10%
- chairbound within 15 yrs, die in 40s.
What is tuberous sclerosis? What are the clinical features?
- autosomal dominant genetic condition
- but 60% occur spontaneously - new mutations.
- formation of hamartomas in many organs: brain, skin, kidneys
- usually presents in childhood with angiofibromas on the skin, epilepsy (cortical tubers), and developmental delay.
- skin changesL facial angiofibromas, ash leaf areas of depigmentation, shagreen patches - thickened skin over sacrum and back, ungual fibromas.
What is neurofibromatosis? What is the difference between type 1 and type 2?
- NF1 and NF2 - both autosomal dominant
- NF2 rarer
- neurofibromas: benign tumours arising from the peripheral nerve sheath
- cafe au lait patches usually seen in 1st year
- dermal neurofibromas appear after puberty
- NF2 - risk of hearing loss
What is hereditary haemochromatosis? What are the presenting features?
- common autosomal recessive disorder of iron absorption - results in iron accumulation- deposits in heart, liver, pancreas, joints, pituitary
- mutations in the HFE gene (chromosome 6)
- more common in males, females present later
- often asymptomatic early on, then non specific lethargy, arhtralgia (often hands)
- incidental high ferritin, or genetic screening of relatives
- hepatomegaly +/- cirrhosis
- skin pigmentation ‘bronze’
- DM
- E.D, testicular atrophy (pituitary dysfunction)
- dilated cardiomyopathy - signs of HF
