Genetics Flashcards
BRCA 1
Lifetime Breast Cancer Risk 80%
Lifetime Ovarian Cancer Risk 50%
BRCA 2
Lifetime Breast Cancer Risk 45%
Lifetime Ovarian Cancer Risk 25%
Trisomy 21
Down’s
- Most common chromosomal abnormality in humans (1 in 700 births)
- 88% is due to nondisjunction of the maternal gamete - 15x more likely age 40 then aged 20
Screening
- ↑ nuchal translucency, ↓PAPP-A , ↑ beta-hCG
- From 14 + 2 to 20 + 0 weeks gestation quadruple test can be used (AFP + oestriol included)
- Screening test determines risk and aids decision for amnio/CVS
Hypotonia, cardiac abnormalities (AV canal defect), GI (duodenal atresia, imperforate anus, Hirschprung’s), conductive hearing loss
+ higher risk Alzheimer’s, AML/ALL, hypothyroid
Trisomy 13
Patau’s
- Affects around 1 in 5,000 live births
- Similar clinical features to Edwards’ syndrome, mortality almost 100% by 1 month
Midline defects (close eyes, cleft), polydactyly, cardaic, renal, omphalocoele, IUGR
Trisomy 18
Edward’s
- Affects 1 in 3000 live births
- increased nuchal translucency, low HCG
- 90%+ detected on 18-20 week ultrasound fetal anomaly scan
- Poor prognosis. Median lifespan 5-15 days
MSK defects, facial defects, cardiac, abdominal (exomphalos, hernia, renal malformations), IUGR
Congenital Adrenal Hyperplasia
Autosomal recessive disorders
-> deficiencies of enzymes involved in mediating the production of cortisol, aldosterone or both. These result in excessive or deficient steroid hormone production.
- 1/17,000 (1/500 Yupik Eskimos)
- 95% of cases are due to 21-hydroxylase deficiency as a result of abnormal CYP21A genes. This results in androgen excess and mineralocorticoid deficiency.
- 5% of cases are due to 11-hydroxylase deficiency.
Presents - neonatal vomiting and shock from salt-loss
- ambiguous genitalia - virilisation of female fetus
- precocious puberty in male
- primary / secondary amenorrhoea with hirsutism and virilisation in late-onset type
- elevated urinary ketosteroids and pregnanetriol
- elevated plasma 17-alpha-hydroxyprogesterone and ACTH
- normal life-span and fertility if promptly identified and treated with steroid replacement
Can diagnose in utero by 17-alpha-hydroxyprogesterone concentration in amniotic fluid or DNA analysis from CVS or amniocentesis
-> maternal administration of dexamethasone
Beta Thalassemia
- 1 in 100,000 global incidence
- Caused by mutation HBB gene Chromosome 11
- Autosomal Recessive Inheritance
- Homozygous B-thalassaemia (Major) produces severe transfusion dependent anaemia
- Heterozygote b-thalassamia (Minor/trait/carrier) produces mild microcytic anaemia
In pregnancy
- 3 months 5mg folic acid before conception
- diabetes, thyroid, cardiology screening, biliary USS, bone density scan
- if major, then regular blood transfusions aiming for pretransfusion Hb >100
- extra scans
- if splenectomy/platelets >600, then get LMWH + aspirin
HNPCC
Hereditary Non-polyposis Colorectal Cancer
- Autosomal dominant inheritance
- Increases risk of colon, gastric and endometrial cancer
- 78% lifetime risk colorectal cancer
- 43% lifetime risk endometrial cancer
Klinefelter’s syndrome
47XXY
- 1 in 1000 live births
- azoospermia and infertility
Tall and thin
Reduced facial & pubic hair
Atrophy of testes
Low libido
Gynaecomastia
Late puberty
Sometimes mild learning disability though most are of normal intelligence
Turner’s syndrome
45XO
- Affects 1 in 2500 female births
- >95% Turner Syndrome conceptions miscarry 1st Trimester
- Often diagnosed fetal anaomoly scan (raised nuchal translucency) or as infants due to heart problems
- In adolescence present with ovarian failure i.e. primary amenorrhoea and failure to develop secondary sexual characteristics
- Clinically short stature, obesity, webbed neck, cardiac, renal, normal intellect
- Biochemically (after age 10) raised FSH and LH
- Thyroid dysfunction also common
Combined chromosomal screening test
Triple test = AFP, hCG and uE3
Quadruple test = AFP, hCG, inhibin-A and uE3
Combined test = PAPP A, hCG and Ultrasound for nuchal thickness
At 11+2 to 14+1 weeks
Then CVS up to 15 weeks, amniocentesis after
Nucleotides
Sugar molecule
- 5 carbon atoms in circular structure forming pentose ring, Deoxyribose in DNA or Ribose in RNA
+ phosphate group attached to carbon 5
+ nitrogenous base attached to carbon 1
- purines - Guanine and Adenine
- pyramidines - Cytosine, Thymine (DNA), Uracil (RNA)
(C to G with 3 hydrogren bonds, A to T/U with 2)
Strands together make nucleic acids RNA/DNA
Genes
Nucleotide stretch coding for polypeptide, determine amino acids therefore function of protein
Exons - coding area, highly conserved between individuals
Introns - longer, not well conserved, spliced out during processing to mRNA (by RNA polymerase)
Chromosomes
22 homologous pairs + 1 pair sex chromosome
Largest is 1, smallest 22
- detected at metaphase, identified with Giemsa staining
- p arm short, q arm long
Cell cycle
4 phases:
G1 (1st gap/grow)
S (synthesis) - chromosome replication diploid or haploid
G2 (2nd gap)
M (mitosis)
Interphase is 1-3 (not mitosis)
Within mitosis - prophase/metaphase/anaphase/telophase
IPMAT
Proliferation genes c-Myc and c-Jun
Inhibition gene p53
Mitosis
Cell division to give 2 identical daughter cells from single parent cell
Prophase - chromatins condense, centrosomes (pair of centrioles) close to nucleus
Metaphase (middle) - nuclei disappear, nuclear membrane disintegrates, centrioles to both poles, mitotic spindles form, chromosomes align
Anaphase (apart) - kinetochore microtubules shorten and separate chromatids
Telophase - chromosomes decondense, reform nuclear membranes, mitotic spindles disappear, then have cytokinesis
Meiosis
To make germ cells, 4 haploid daughter cells from a single diploid parent cell
Meiosis 1 - separating to make 2 haploid cells
Meiosis 2 - similar to mitosis
Structural chromosome abnormalities
Translocation - balanced or unbalanced
eg Robertsonian - fusion of long arms of two acrocentric chromosomes
Deletion
- DiGeorge 22q11 - immune deficiency, parathyroid, autism, cardiac, cleft
- Angelman 15q11-13 Mat deletion - happy, macroglossia, ataxia, seizures, LD
- Prader-Willi 15q11-13 Pat deletion - obesity, hypogonadism, hypotonia
Autosomal dominant conditions
Inheritance 1:2
eg myotonic dystrophy, Huntington’s, Neurofibromatosis, Marfan’s, Osteogenesis imperfecta, PCKD, VWD, Tuberous sclerosis
Autosomal recessive conditions
Inheritance 1:4 if both parents carriers
eg CF, sickle cell disease, thalassaemia, phenylketonuria, CAH, Wilson’s
X-linked recessive conditions
Inheritance 1:2 in sons of female carriers affected
Daughters of all affected males are carriers
No male to male transmission
eg Duchenne MD, Fragile X, G6PD deficiency, haemophila A and B
X-linked dominant conditions
Inheritance 1:2 of affected females, males and females both affected
Usually manifests severely in males - pregnancy loss or neonatal death
eg Rett syndrome, Vitamin D deficient rickets
Mitochondrial inheritance conditions
Mitochondrial DNA by maternal line (sperm do not contribute to zygote beyond nuclear DNA)
Can affect both sexes, but only passed on by affected mothers
eg Leber’s hereditary optic neuropathy, Leigh’s syndrome
Tuberous sclerosis
Autosomal dominant
Causes tumours to grow in brain + other organs
TSC1 gene (ch9, coding hamartin) or TSC2 gene (ch16, coding tuberin) mutations - so mutation in tumour supressors
LD, epilepsy, cardiac, renal, skin (butterfly rash, ash-leaf spots, shagreen patches), brain
Cystic fibrosis
Autosomal recessive
Exocrine secretion, increased chloride in sweat
1:2000, 1:25 caucasian carriers
CFTR gene - on ch7, usually F508del (produces chloride ion protein responsible for anion transport)
Excess mucus production blocking ducts of mucus secreting organs - recurrent chest infections, infertility, pancreatitis, cirrhosis, intestinal obstruction, osteoporosis, diabetes
+ congenital absence of vas deferens in males 98% infertility
Sickle cell disease
Autosomal recessive
HbSS homozygous or HbAS heterozygous
Point mutation on beta globulin chain of Hb
Single base change GAG to GTG, so hydrophobic protein made instead of hydrophilic
Loss of RBCs due to loss of elasticity and sickling, short life span 10-20 days, haemolysis in spleen
Blood film shows sickling, + Howell-Jolly bodies
Vaso-occlusive crisis
Acute chest syndrome - fever, chest pain, SOB, pulmonary infiltrates on XR
Aplastic crisis - parvoB19 trigger
Splenic sequestration crisis
Haemolytic crisis - esp if G6PD also
Treat - cyanate, hydroxyurea, analgesia, penicillin, vaccinations, blood transfusion, BM transplant
Thalassaemia
Reduced rate in synthesis of 1 of globulin chains making Hb
More in mediterranean/Arab/Maldives
Anaemia due to hypochromia (low intracellular Hb), excess unimpaired chain
See microcytosis, target cells, hypochromia
Alpha thalassaemia
There are 4 alpha globin chains
1 affected - silent carrier
2 affected - trait - mild hypochromic anaemia
3 affected - haemoglobin H disease, moderate anaemia with splenomegaly
4 affected - Bart’s hydrops - in utero death
See tissue hypoxia, hydrops fetalis
In fetus start seeing distree after 12 weeks when Hb Portland is replaced by Hb Barts (higher affinity to oxygen so inhibit delivery to tissues)
Beta thalassaemia
1:10,000 in UK, 1:7 in Cyprus
Major - homozygous
Minor/trait or intermedia - heterozygous
Fatigue, anaemia, jaundice, SOB, skeletal abnormalities, hepatosplenomegaly, haemochromotosis
Usually present at 6months, when fetal Hb to adult Hb
Treat for major - blood transfusions, folic acid, vitD and calcium, chelation therapy, splenectomy, BM transplant
Chromosome shapes
METACENTRIC - have the centromere in the middle (1, 3, 16, 19, 20)
ACROCENTRIC - have the centromere close to one end (13, 14, 15, 21, 22) -these are the chromosomes usually involved in balanced translocations
SUB-METACENTRIC - have centromere in-between
Chromosomes have a short (p = petit) and a long (q) arm??
Histones
Basic nuclear protein around which the DNA molecule is tightly bound
- makes up about 50% of the mass of a chromosome (1:1 histone:DNA)
- rich in lysine or arginine (~25%, basic amino acids)
- the genes coding for histone protein are clustered and tandemly repeated 30-40 times in humans
Biochemical techniques
Western blotting - used to detect protein
Northern blotting - used to detect RNA
Southern blotting - used to detect specific DNA sequences
PCR used to amplify DNA sequences
G6PD
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
X-linked recessive (so males!)
- deficiency of erythrocyte glucose-6-phosphate dehydrogenase. Enzyme plays key role in Pentose phosphate pathway, catalysing conversion of glucose-6-phosphate to 6-phospho-gluconolactone
- may be asymptomatic, or neonatal jaundice, chronic haemolytic anaemia, haemolysis induced by eating fava beans, sulphonamides, primaquine and infection
- female carriers may suffer haemolytic crises
Myotonic dystrophy
- autosomal dominant
- unstable length mutation in the number of CTG repeats - correlation between the length of the repeats and severity of the disease
- the length of the repeat may change during transmission, altering the severity of the disease from one generation to the next
- no neonatal disease if the father has the disease. With maternal disease, there is a 20% risk of neonatal death or severe neonatal hypotonia and mental handicap
- clinical features include frontal balding, distal muscle and sterno-mastoid weakness, gonadal atrophy in males, difficulty relaxing a clenched fist, cardiac conduction defects and retinopathy
- pre-natal diagnosis by direct DNA analysis
Phenylketonuria
- autosomal recessive
- deficiency of phenylalanine hydroxylase
- if early low phenylalanine diet, associated with normal life span although some degree of learning disability may be present
- after childhood (6-8years), the brain is less susceptible to the harmful effects of high phenylalanine levels
- need to return to low phenylalanine diet in pregnancy, or risk of fetal structural abnormalities including microcephaly
- causes high blood and urine phenylalanine levels
- neonatal screening using the Guthrie test
Muscular dystrophy
Duchenne
- X-linked recessive
- null mutation resulting in absence of dystrophin on muscle biopsy
- onset in childhood (by age of 5) with proximal muscle weakness, calf pseudo-hypertrophy; mild learning disability in 25%, majority wheelchair bound by age 12 with death in 20s.
Becker
- X-linked recessive
- reduced dystrophin on muscle biopsy
- onset in late childhood, calf pseudo-hypertrophy. Wheelchair bound by age 25, life-span may be normal - better prognosis than Duchenne
Pre-natal diagnosis for Duchenne / Becker muscular dystrophy by direct DNA analysis (CVS / Amnio)
Homocystinuria
- autosomal recessive
- disorder of the metabolism of methionine due to a deficiency of cystathionine beta synthase or methionine synthase
- can also be caused by a deficiency of vitamins B6, B12, or folate
-> multi-systemic disorder of the connective tissue, muscles, the CNS and CVS - accumulation of the amino acid homocysteine in the serum and increased excretion of homocysteine in the urine
Flushed cheeks
Tall, thin build resembling Marfanoid habitus
Long limbs
Pes cavus
Genu valgum
Pectus excavatum and Pectus carinatum
Intellectual disability
Seizures
Psychiatric disease
Eye abnormalities
Vascular disease
Haemophilia
A - factor VIII deficiency
B - factor IX deficiency
- both are X-linked recessive and clinically indistinguishable
- spontaneous bleeding into joints / soft tissue or following trauma
- treated by factor VIII or IX replacement
- male fetus inherits Y chromosome from father and therefore cannot be affected if the father has the disease. 50% risk of male fetus being affected if the mother is a carrier (inherits one of 2 X chromosomes).
Androgen insensitivity syndrome
X-linked recessive
- mutation in androgen receptor gene
- female phenotype, normal breast development, absent uterus with blind-ending vagina; paucity of pubic and axillary hair
- testes found in abdomen or inguinal canal
- increased risk of gonadoblastoma *
- infertility
- karyotype 46XY
Osteogenesis imperfecta
- genetic defect in collagen metabolism
Type I - autosomal dominant, associated with recurrent fractures, blue sclera, otosclerosis leading to conduction deafness. Normal life span
Type II - variable inheritance with a 3% recurrence risk - causes perinatal death with multiple fractures at birth
Alpha-1 antitrypsin
- autosomal recessive
- carrier frequency 3% in Caucasians
- Z-allele is a point mutation which interferes with the release of anti-trypsin from hepatocytes
- diagnosis by protease inhibitor activity assay or DNA analysis (CVS or amnio)
- associated with juvenile cirrhosis, emphysema
Marfan syndrome
- Autosomal dominant - 50% risk of offspring inheriting the condition
+ 25% caused by new mutation - associated with lens subluxation, aortic aneurysm, arachnodactyly, long limbs and joint laxity
- average life-span 40-50 years
Von Willebrand disease
- mostly autosomal dominant although some variants may be autosomal recessive
- defect in von Willebrand factor (vWF), which promotes platelet adhesion to sub-endothelium and binds and stabilises factor VIII
- factor VIII activity may be reduced
-> prolonged bleeding time and reduced platelet aggregation with ristocetin - infection, stress, inflammation, physical exercise and recent surgery and pregnancy cause raised vWF and factor VIII levels
Haemoglobin electrophoresis
- used as a screening test to identify variant and abnormal haemoglobins, including HbA1, HbA2, HbF, HbC, HbS
Should be:
HbA 1: 95%-98%
HbA 2: 1.5%-3.5%
HbF: < 2% (age-dependent)
HbC: Absent
HbS: Absent
Urea cycle
In liver, urea then excreted by kidneys
Rate limiting step controlled by enzyme carbamoyl phosphate synthetase I
One turn of the urea cycle:
- consumes 2 molecules of ammonia
- consumes 1 molecule of carbon dioxide
- creates 1 molecule of urea ((NH2)2CO
- regenerates a molecule of ornithine for another turn
Genetic conditions predisposing to ca
Neoplasms
- Retinoblastoma - autosomal dominant, often bilateral. Increased susceptibility to second tumours especially osteosarcoma. Locus 13q14
- Familial poliposis coli - autosomal dominant. May be associated with osteomas, lipomas and fibromas (Gardner’s syndrome)
- Multiple endocrine neoplasia type I - autosomal dominant, adenomas of the pituitary, parathyroid and islet cell
- Multiple endocrine neoplasia type II - autosomal dominant, medullary carcinoma of the thyroid, phaeochromocytoma and parathyroid tumour
Pre-neoplastic conditions
- Neurofibromatosis - autosomal dominant, gliomas of the brain and optic nerve, acoustic neuromas, meningioma, phaeochromocytoma
- Tuberous sclerosis - autosomal dominant, glial tumours, harmatomas
- Xeroderma pigmentosa -autosomal recessive, basal and squamous cell carcinoma of the skin, malignant melanoma
- Fanconi’s anaemia - autosomal recessive, acute leukaemias
- Ataxia telangiectasia - autosomal recessive, acute leukaemia, lymphoma and breast cancer in females
