Clinical genetics Flashcards
What are nucleotides made up of
Sugar molecule, nitrogenous base, phosphate group.
What does the nucleotide sugar molecule look like?
5 carbon atoms, pentose ring.
DNA = deoxyribose
RNA = ribose
Where is the base attached on the sugar of a nucleotide?
on carbon 1
Where is the phosphate attached on the sugar of a nucleotide?
carbon 5
How many types of nitrogenous base are there and what are they called
purines and pyrimidines
Purines are…
Purines - Guanine, Adenine
Pyrimidines are..
Pyrimidines - Cytosine and Thymine (DNA) or Uracil (RNA)
Nucleic acids
Long nucleotide chains - DNA (ds) RNA (ss)
DNA
ds helix held together by a hydrogen bond
DNA bond
phosphodiesterase - 5’ to 3’
Steps of replication of DNA
DNA helicase - unwinds ds DNA
DNA polymerase - copies DNA
DNA ligase - winds by the DNA
Types of RNA
mRNA - transcription
rRNA - ribosomal
tRNA - transfer - involved in translation
Codons
- made of RNA in triplets
- each code for only one amino acid
maximum 64 codons available
Genes are made up of
Stretches of nucleotides that code for a polypeptide
Genes have two regions:
- Exons (coding area)
2. Introns (non-coding area) - mRNA splices out this area during processing
Chromosomes comprised of
2 chromatids attached at a centromere
How can you see chromosomes
Giemsa Staining at metaphase
Nomenclature of arms
p = short arm q = long arm
Protein synthesis
- Transcription :
DNA is transcribed to mRNA by RNA polymerase.
DNA read 3’ to 5’; mRNA is transcribed 5’ to 3’
- Translation:
mRNA is translated to amino acids by ribosomes
Polymerase Chain Reaction (PCR)
What is it?
What does it require?
PCR amplifies selected areas in a DNA strand Needs: 1. 2 primers 2. 4 deoxyxnucleotides 3. Taq polymerase
Is a logarithmic amplification
Types of blotting
Southern blotting - DNA
Northern blotting - RNA
Western blotting - protein
Phases of cell cycle
Interphase - G1, synthesis and G2
Mitosis - itself made up of four phases
Where does chromosome replication occur?
S phase
Proliferation genes
c-Myc :
c-Jun :
Inhibiting gene
p53
Stem cells - potency
totipotent - can divide in to both embryonic and extra embryonic stem cells pluripotent multipotent oligopotent unipotent
Mitosis
Nuclear division
- prophase - condensation of chromatins
- metaphase - mitotic spindles form, align at plate
- anaphase - chromatids separate
- telophase - chromosomes decondense, new nuclear membranes
Cytokinesis
Meiosis
Production of germ cells - 4 for every 1 parent cell
Meiosis 1 - creates two haploid cells
- prophase 1
- metaphase 1
- anaphase 1
- telophase 1
Meiosis 2 - similar to mitosis but homologous chromosomes align at the metaphase plate
2 principles of Mendels Law
Law of segregation - each gamete only receives 1 allele for each gene
Law of independent assortment - alleles of different genes assort independently of one another during gametogenesis
models of gene inheritance
autosomal dominant /recessive
x-linked dominant/recessive
mitochondrial
Types of chromosomal abnormalities
- aneuploidy (change in number of chromosomes)
- structural (translocation, inversion, deletion, duplication, insertion)
Down’s syndrome
Genetics
Prevalence
Trisomy 21
1:700 live births
Increased nuchal translucency
Features of T21
Dysmorphic features (small ears, up slanting palpebral fissures, flat facial profile, brachycephaly)
Hypotonia
Cardiac abnormalities
GI tract - duodenal atresia, imperforate anus,
Hirschprungs
Conductive hearing loss
T21 have increased risk of:
Alzheimer’s
AML/ALL
Hypothyroidism
Maternal age risk of T21
25: 1:1500
30: 1:900
35: 1:350
40: 1:100
45: 1:30
50: 1:11
Cut off for invasive screening 1:250
Edward’s syndrome
Genetics
prevalence
T18
1:3000, Male to female 1:2
T18 Features
Increased nuchal translucency
Musculoskeletal defects:
- limbs
- rocker bottom feet
- overlapping fingers
Facial defects
- micrognathia
- cleft lip/palate
Cardiac
- VSD
- ASD
- PDA
Abdominal
- exomphalos
- inguinal hernia
- diaphragmatic hernia
- renal malformations
IUGR
T18 mortality rates
by 1 month: 30%
by 2 months: 50%
by 1 year: 90%
Patau’s syndrome
Genetics
prevalence
T13
1:5000 live births
T13 features
Midline defects - Hypotelorism (close eyes) - Holoprosencephaly - Cleft lip/palate - Scalp defects Polydactyly Congenital heart defects Renal abnormalities Omphalocele IUGR
T13 mortality
100% by 1 month
Sex chromosome aneuploidies
Kleinfelter’s 47XXY
Turner’s 45X0
Lyon’s hypothesis
Explains how females have have XX and the same effect as males X
Barr body - is inactivated condensed X chromosome, present if >2 X chromosomes in the cell
Inactivation of one of the X chromosomes happens at 15-16 days gestation.
Turner’s Syndrome
Genetics
Prevalence
45X0
1:2500
Turner’s Syndrome
Features
Raised nuchal translucency Cystic hygroma Lymphoedema Neck webbing Short stature Wide carrying angle of arms Shield shaped chest Coarctation of the aorta Gonadaldysgenesis Renal anomalies - eg: horseshoe kidney
Intellectually normal
Risk of gonadoblastoma
Kleinfelter’s syndrome
Genetics
Prevalence
47XXY
1:1000
Kleinfelter’s syndrome
Features
Tall
Hypogonadotrophtrophic hypogonadism
Infertility
Translocation
Exchange of two segments of chromosome between non-homologous chromosomes
- balanced (even exchange so no chromosomes are gained or lost)
- unbalanced (missing or extra genes)
Deletion - examples
DiGeorge’s
Angelman syndrome
Prader-Willi
DiGeorge’s
DiGeorge’s
- Immune deficiency
- Parathyroid dysfunction - hypoCa
- Autism
- Congenital heart disease
- Cleft lip/palate
Angelman
Happy disposition Macroglossia Ataxia Seizures Learning difficulties
Prader-Willi
Obese
Hypogonadism
Hypotonia
Types of genetic disorders
Autosomal
- dominant
- recessive
X-linked
Mitochondrial
Autosomal dominant
male : female = equal
Inheritance = 1:2
Autosomal recessive
Inheritance 1:4 if both parents are carriers
X-linked recessive
male = affected females = carriers Inheritance = 1:2 sons of carrier females Inheritance = all daughters of affected males are carriers
X-linked dominant
Inheritance = 1:2 offspring of affected females
Severe manifestation in males - miscarriage/IUD of male fetuses
Mitochondrial
Inherited through the maternal line
Affects both sexes but only passed on maternally
Tuberous Sclerosis
Genetics
Multisystem - causing tumours to grow in the brain and other vital organs
either TSC1 (chromosome 9, encodes harmatin) or TSC2 (chromosome 16, encodes tuberin)
Harmatin and tuberin are suppressors of tumour growth
Tuberous Sclerosis
Clinical features
learning difficulties
epilepsy
cardiac rhabdomyomas
renal angiomyolipomas
skin manifestations - angiofibromas, hypomelanotic macule, shagreen patches, ungual fibromas
brain abnormalities - subepydermal nodules, cortical tubers
Cystic fibrosis
Genetics
Exocrine secretion Inc chloride in sweat 1:2000 Carrier rate 1:23 Mutation in CFTR gene (chromosome 7) Most common is F508
Cystic fibrosis
Clinical features
Viscous mucus production Recurrent chest infections, poor alveolar gas exchange Infertility - congenital absence of vas deferent, thickened cervical mucus Pancreatitis Cirrhosis Intestinal obstruction Malabsorption (ADEK vitamins) Osteoporosis Diabetes
Sickle cell disease
Genetics
Point mutation in beta chain of Hb - meaning single base change adenine to thymine - causing glutamic acid to valine (aa) (hydrophilic to hydrophobic) 1:500 in London Homozygous (HbSS) Heterozygous (HbAS) Short life span of RBC (10-20/7)
Sickle cell disease
Complications
Infarction - Hyposplenism, autosplenectomy
Emboli - Stroke, Pul HTN
Ischaemia - Avascular necrosis of the head of the femur, chronic renal failure
Haemolysis - jaundice, cholelithiasis
Infection - osteomyelitis, overwhelming post splenectomy infection
In Preg - IUGR, pre-eclampsia, miscarriage
Sickle cell disease
types of crisis
Vado-Occlusive crisis Acute chest syndrome (fever, pain, SOB) Aplastic crisis (parvo B19) Splenic sequestration crisis Haemolytic crisis
Sickle cell disease
Treatment
Cyanate - irreversible inhibition of sickling
Hydroxyurea - reactivates fetal Hb
Analgesia
Penicillin
Vaccination for encapsulated organisms (haemophilia influenza, Strep pneumoniae, N meningitides)
Blood transfusion/exchange transfusion
Bone marrow transplant
Thalassaemia
Genetics
Reduced rate of synthesis of one of the globulin chains - alpha, beta, delta, E thal, S thal, C thal.
Hypochromia - low amount of Hb
Anaemia - excess unpaired chain leads to reduced RBC survival
Alpha-thalasseamia
Clinical features
1 chain - silent carrier
2 chains - trait - mild hypochromic anaemia
3 chains - Hb H disease, moderate anaemia and splenomegaly
4 chains - Bart’s hydrops - IUD
Tissue hypoxia, Hydrops fettles
Initially fetus OK as using Hb Portland. Distress after 12/40 when using Hb Barts
Beta-thalassaemia
Prevalence
UK 1:10,000
South Asia 3:100
Cyprus 1:7
Beta-thalassaemia
Classifications
Major - homologous
Minor/trait - genetically heterozygous
Intermedia - genetically heterozygous
Beta-thalassaemia
Clinical features
Fatigue
Anaemia
SOB
Jaundice
Skeletal deformities due to increased erythropoiesis
Hepatosplenomegaly due to extramedullary haematopoiesis
Haemochromatosis due to excess iron absorption from the gut
Delayed physical and sexual development secondary to haemochromatosis
Beta-thalassaemia major
Treatment
Regular blood transfusion Folic acid supplementation Vit D/Ca supplements Chelation therapy - remove excess iron following transfusions Splenectomy Bone marrow transplant Cord blood transfusion
Cystic fibrosis on which chromosome
7
trisomies and microdeletions
P 13 A 15 Pr 15 E 18 D 21 Di 22
Signs of T21 on quad test
reduced AFP - smaller size
bHCG elevated
Signs of neural tube defect on quad test
high AFP - flows out of neural tube
Normal PAPPA
invasive diagnostic testing
CVS from 11 weeks
amnio from 15 weeks
