Original Genetics Flashcards
What is the haploid number of chromosomes?
23 - as is found in the germ cells
What is the diploid number of chromosomes?
46 - as is found in the somatic cells
What are the different types of chromosomes?
1) Metacentric chromosome - when the short and long arms are approx. equal length
2) Submetacentric chromosome - when one arm is obviously longer than the other
3) Acrocentric chromosome - when the centromere is situated at the top of chromosome
What are the chromosome arms called?
p and q arms
How do somatic cells divide?
Mitosis
How do germ cells divide?
Meiosis
How does meiosis occur?
Meiosis I - homologous chromosome pairs cross over then separate (still diploid)
Meiosis II - sister chromatids separate (now haploid)
Produces sperm/ova
What are the most common trisomy conditions?
Down syndrome - trisomy 21
Edward’s syndrome - trisomy 18
Patau syndrome - trisomy 13
Klinefelter syndrome - 47XXY
What is the most common monosomy?
Turner syndrome - 45X
What proportion of Down syndrome is accounted for by non-disjunction?
95% - when there is 3 separate copies of chromosome 21
What are the features of Down syndrome?
Learning difficulties
Atrioventricular septal defect
Upslanting palpebral fissures
Epicanthic folds
Flat midface
What are the features of Edwards syndrome?
Profound learning difficulties
Congenital heart disease, commonly VSD
Facial clefts
Clenched hands
Rocker-bottom feet
Spina bifida
What are the features of Patau syndrome?
Profound learning difficulties
Cardiac - VSD/ASD
Left lip/palate
Holoprosenecephaly
Microphthalmia/anophthalmia
Polydactyly
Scalp defects /Omphalocele/Renal anomalies
What is more common, Edwards or Patau?
Edwards
What proportion of Turner’s syndrome foetuses make it to term?
1%, they don’t tend to survive due to fetal hydrops
What is the consequence of balanced reciprocal translocation?
Usually there is no phenotypic consequences
What are the possible outcomes for a woman with a balanced reciprocal translocation?
1) A normal pregnancy with normal karyotype
2) A normal pregnancy with the familial balanced reciprocal translocation
3) A spontaneous miscarriage owing to an unbalanced product of the familial translocation
4) A pregnancy that goes to term but the child has a high likelihood of learning difficulties and possibly other congenital anomalies associated with an unbalanced product of the familial reciprocal translocation
What do you do if you detect an unbalanced reciprocal translocation prenatally?
Counsel parents that it is likely to be associated with fetal anomaly
What do you do if you detect balanced reciprocal translocation prenatally?
Karyotype the parents - ?familial/de-novo
- If it is familial and the parent carrying the balanced translocation is healthy, the baby is unlikely to have problems.
- If it is de novo, it may be associated with problems and a microdeletion should be investigated for using an array comparative genomic hybridisation (aCGH)
What is imprinting?
The process by which one parental allele is preferentially silenced according to its parental origin
What imprinting disorder does paternal UPD15 (uniparental disomy) cause?
Angelman syndrome
What imprinting disorder does maternal UPD15 cause?
Prader-Willi syndrome
What are the different types of mutation?
1) Missense mutation -1 base sub
2) Frameshift mutation -1+ base insert/deleted
3) Nonsense mutation -1 base sub-> short protein
4) Splice site mutation - intron/extron
What is a missense mutation?
Single base substitutions occurring in a coding region of the disease
What is a frameshift mutation?
One or more bases (not a multiple of 3) are inserted/deleted –> different stop codon placement –> truncated proteins
What is a nonsense mutation?
A single base substitution –> premature stop codon –> truncated protein
What is a splice site mutation?
When there is a mutation to the nucleotides.
Introns removed from primary transcript and exons joined at splice site
What are the common triplet repeat conditions?
1) Fragile X syndrome
2) Huntington’s
3) Myotonic dystrophy
What features are common to triplet repeat conditions?
1) Variability of phenotype
2) Anticipation - progression in triplet repeat size and phenotype severity as the repeat is passed on
3) Parent-of-origin effect - the triplet may expand if passed on by the mother rather than the father or vice versa
What are some common microdeletion syndromes?
1) Cri du chat
2) Williams
3) DiGeorge
What’s the lifetime risk of breast/ovarian cancer in BRCA1?
Breast = 80%
Ovarian = 40%
What’s the lifetime risk of breast/ovarian cancer in BRCA2?
Breast = 45%
Ovarian = 15%
What are the characteristics of autosomal dominant pedigrees?
1) Individuals in each generation are affected
2) Males and females affected in roughly equal numbers
3) Both men and women can have affected children
What are the characteristics of autosomal recessive pedigrees?
1) Only one generation is affected
2) Parents of affected children are consanguineous
What are the characteristics of x-linked recessive pedigrees?
1) Only male individuals are affected, if females are affected they may have a milder phenotype
2) No male-to-male transmission
3) The condition may seen to skip generations
What are the characteristics of x-linked dominant conditions?
Results in spontaneous loss or pregnancy or early neonatal death in males. Therefore, they seem to be restricted to live female individuals
What are some examples of mitochondrial disease?
1) MELAS - mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
2) Leigh’s disease - subacute necrotising encephalomyopathy
3) MERRF - myoclonic epilepsy with ragged red fibres
What is nuchal translucency?
The songraphic appearance of subcutaneous fluid found at the back of the fetal neck between weeks 11 and 14.
What does the combined test comprise of?
The NT scan + b-hCG + PAPP-A
What is the detection rate of trisomy 21 when using NT in isolation?
70-75%, with a 5% false-positive rate
What is the detection rate of trisomy 21 with the combined test
90%
What may be seen in a Trisomy 18 pregnancy?
Polyhydramnios or oligohydramnios
What are the AFP/b-hCG levels in Down’s syndrome?
AFP = reduced
b-hCG = increased
What may cause reduced PAPP-A?
Aneuploidy, e.g. Down’s, or IUGR
From what gestation can CVS be performed?
Week 11
From what gestation can amniocentesis be performed?
Week 15
On what chromosome is BRCA1 found?
Chromosome 17
On what chromosome is BRCA2 found?
Chromosome 13
What is the inheritance type of the BRCA gene?
Autosomal dominant
What type of inheritance does ‘familial’ Down’s syndrome refer to?
Robertsonian translocation
Which chromosomes can Robertsonian translocations occur on?
Chromosomes 13, 14, 15, 21 and 22 only
What is seen in a fetus with a complete absence of a-globulin chains, as with those with alpha-thalassaemia?
Hydrops fetalis
What is the incidence of PKU in the UK?
1/14000
What are the neurotoxic byproducts of phenylalanine?
Phenylpyruvic acid and phenylethylamine
When should the heel prick test be performed?
> 12 hours after birth
What are the 3 types of PKU?
1) Type 1 (autosomal recessive); 2) Type 2; 3) Malignant PKU
What is the detection rate of Down’s using NT alone?
70%
What is the detection rate of Down’s in the 1st trimester using both NT and serum screening?
85% detection rate
5% false +ve rate
What is the risk of Down’s in a woman >/= 45?
> 1/50
What is the risk of Down’s in a woman @ 20 years old?
1/1500
What is the most common enzyme deficiency causing CAH?
21-hydroxylase
What is 21-hydroxylase deficiency caused by?
Abnormal CYP21A genes
What is the pattern of serum markers in Down’s?
PAPP A, AFP and uE3 = down
inhibin A and b-hCG = up
What is the pattern of serum markers in Edward’s?
PAPP A, AFP, UE3, inhibin A and b-HCG = down
What should be offered to all women with beta-thalasaemia in pregnancy?
1) Folic acid 5mg from 3/12 prior to conception
2) Specialist cardiac assessment at 28/40
3) Serial fetal biometry scans every 4/52 from 24/40
4) Regular blood transfusion aiming for a pre-transfusion Hb of 100
5) If have undergone splenectomy and have a plt count >600, they should have LMWH + 75mg aspirin
How is beta-thalasaemia inherited?
Autosomal recessive
What does beta-thalasaemia cause?
Major (homozygous) = severe transfusion dependant anaemia
Minor (heterozygous) = mild microcytic anaemia
What does the triple test consist of?
AFP
b-hCG
uE3
What does the quadruple test consist of?
AFP
b-hCG
uE3
inhibin A
At what gestations can the quadruple test be used?
14+2/40 —> 20+0/40
What does the combined test consist of?
NT scanning
b-hCG
PAPP-A
At what gestations can the combined test be used?
11+2/40 —> 14+1/40
At what gestation could the mid-trimester anomaly scan occur?
18+0/40 —> 20+6/40
What proportion of breast cancers are caused by BRCA?
5%
What proportion of inherited cancers are caused by BRCA?
25%
How is Noonans inherited?
Autosomal dominant
How is Cri-du-Chat inherited?
Microdeletion of chromosome 5
What is the inheritance pattern of adult PKD?
Autosomal dominant
At what stage of meiosis is the oocyte after ovulation?
Metaphase II
How many genes in the human genome?
20,000
What is the risk of non-disjunction at age 40?
1/100
What is the risk of non-disjunction at age 45?
1/30
What chromosomes are most commonly involved in reciprocal translocations?
Chromosome 11 and 22
What chromosomes are involved in Robertsonian translocations?
13; 14; 15; 21 and 22
What are the most common Robertsonian translocations?
Fusion of chromosome 13 to 14
Fusion of chromosome 14 to 21
What is the method by which microdeletions may be detected?
Microarray aCGH
What are some common autosomal dominant conditions?
- Tuberous sclerosis
- Marfan’s
- HNPCC
- Neurofibromatosis 1
- Huntingtons
- Achondroplasia
- Autosomal dominant polycystic kidney disease
What are some common X-linked dominant conditions?
1) Incontinentia pigmenti
2) Rett syndrome
What may cordocentesis be used for? And when?
From week 18
Can be used to assess anaemia and diagnose prenatal infection
What is the most common trisomy in miscarried fetuses?
Trisomy 16
What does the ‘double bubble’ sign suggest?
Duodenal atresia, which in itself suggests Down’s syndrome
What type of chromosome is the X chromosome?
Metacentric chromosome
How is vitamin D resistant rickets inherited?
X-linked dominant
What is a genetic cause of hypergonadotrophic hypogonadism?
Klinefelters
What are nucleotides made up of?
A sugar
A nitrogenous base
A phosphate group
How many carbons on each sugar? And what are the different types of sugar?
5 carbons to each sugar
Different types = deoxyribose (for DNA), ribose (for RNA)
Where on the sugar does the nitrogenous base attach to form a nucleotide?
Base attaches to carbon 1
Where on the sugar does the phosphate group attach to form a nucleotide?
Phosphate group attaches to carbon 5
How many bonds form between C and G?
3 H bonds
How may bonds form between A and T/U?
2 H bonds
What are the purine nitrogenous bases?
A
G
What are the pyrimidine nitrogenous bases?
T
C
U
pyrimidine ‘(nice) To Cee U’
What is the largest chromosome?
Chromosome 1
What is the smallest chromosome?
Chromosome 22
What enzymes are involved in DNA replication?
Unwinding of strands - DNA helicase
Copying of strands - DNA polymerase
Winding back of strands - DNA ligase
When does the majority of non-disjunction occur?
70% at meiosis 1
Which cardiac defect is associated with Turner’s syndrome?
Coarctation of the aorta
What is a Barr body?
An inactivated X chromosome present if there are >2 X chromosomes in a cell
What clotting factor is deficient in Christmas disease?
XI
What clotting factor is deficient in Haemophilia A?
VIII
Haemophilia A - eight/’Aight’
Wha clotting factor is deficient in Haemophilia B
IX
Goes in order:
Haemophilia A - eight
Haemophilia B - nine
Where is the CF mutation mutation located?
Mutated CFTR gene on chromosome 7
Most common mutation = F508
What causes aplastic crisis in sickle cell disease?
Parvovirus B19
What are the features of hyposplenism seen on blood film in sickle cell disease?
Codocytes
Howell-Jolly bodies
Where is the highest incidence of thalassaemia in the world?
Maldives
What is Bart’s hydrops?
A type of alpha thalassaemia whereby 4 genes are affected (severity is determined by the number of genes affected) - it causes in utero death
What is the incidence of beta thalassaemia in the UK?
1/10,000
Which hormones are elevated in Turner’s syndrome?
LH and FSH are elevated in Turner’s syndrome
What does non-disjunction of chromosomes during meiosis cause?
Aneuploidies (trisomy/monosomy)
