Lecture 4- Genetics and Human Development Flashcards
When can you carry out genetic testing?
1. Before birth
a) Embryo biopsy (Preimpantation Genetic Diagnosis PGD)
b) Fetal DNA in maternal blood – cell free DNA
c) Ultrasound
d) Chorionic Villus sampling
e) Amniocentesis
After birth
- Neonatal (newborn)
- During childhood and into adulthood
- Predictively or presymptomatically
What are the details about the embryo biopsy?
-get eggs, fertilise, have an embryo, wait until 8 cells then take 1 out and run tests, it seems taking one out is fine doesn’t seems to cause detriment to the foetus
What are the details about fetal DNA in maternal blood?
- For some time known fetal cells are in maternal circulation but technically difficult to work with
- six weeks into the pregnancy, can take the cells and can figure out the sex of the foetus, maybe= lot of errors as the foetal cells remains in circulation 21 years
- the main problem is that the fetal cells are extremely rare and may persist for years after prior pregnancies so you could be testing cells from a previous pregnancy
What is the cell free DNA and how is that used in genetic testing?
- By comparison, fetal “cell-free (cf)” nucleic acids not contained within cell membranes (cfDNA and cfRNA) are plentiful in the maternal circulation and unique to the current pregnancy. It has been shown that it is possible to noninvasively sequence the entire fetal genome
- once pregnancy is over the DNA disappear
- the mother gives 10ml of blood at 7 weeks of pregnancy -the DNA probably off the placenta
- Circulating cell free fetal DNA, which comprises approximately 3–13% of the total cell free maternal DNA, is thought to be derived primarily from the placenta, and is cleared from the maternal blood within hours after childbirth -Has been used to diagnose aneuploidies
What are the details about NIPD (non invasive prenatal diagnosis) ?
- use maternal blood
- take 10ml from the mother at 7 weeks into the pregnancy
- can test sites to determine aneuploidies and mutations in fetus
- can use markers on the chromosome and can do multiplex sequencing = multiplexing
- revolution in testing as non invasive!
What is the Triple Test of maternal blood?
- Three specific substances: AFP, hCG, and Oestriol.
1. AFP: alpha-fetoprotein is a protein that is produced by the fetus (high - indicator of Neural Tube Defect eg.,spina bifida.)
2. hCG: human chorionic gonadotropin is a hormone produced within the placenta
3. Oestriol: oestriol is an estrogen produced by both the fetus and the placenta  - this has been available for some time
- there are exceptions and outside the range cases
- take the three measurements and take into account the age of the mother, then calculate the probability of a trisomy
- depending on stage of pregnancy can be higher or lower in trisomy 21
- done at 15-18 weeks
How do you estimate the risk of a trisomy using the triple test of maternal blood?
- Age of mother
- Ultrasound
- Blood test:
alpha-fetoprotein (AFP) ); low on Trisomy 21 (high with neural tube defects) human chorionic gonadotropin (hCG) (low in Trisomy 21) oestriol (high in Trisomy 21) - (trisomy 18 low in all)
-then work out a probability for the child having some problem, then if 1/100= more invasive testing
When do you have ultrasound?
- 11-12 weeks, then at 20 weeks (sex as wel)
- look for a nuchal translucency to asses if more testing is needed
What is nuchal translucency?
- Nuchal translucency is a collection of fluid under the skin at the back of your baby’s neck. -It can be measured using ultrasound: between 11 weeks and 13 weeks
- All babies have some fluid at the back of their neck. But many babies with Down syndrome have an increased amount.
What is chorionic villus sampling?
- Chorion is a membrane derived from the same tissue as the embryo
- take a tissue sample, usually trans-vaginally, guided by ultrasound
- it is usually done at 12 weeks, so by the time you know if something is likely wrong it is too late but many older mothers do this test before anything else as they are higher risk
How much chorion do you need in chorionic villus sampling?
- 10 - 30mg chorion required
- direct test (15-20mg) 2-8days
- short term (1 mg) 24-48 hours
- long term (2-4 weeks)
- separate maternal and fetal tissue - (contamination problem)
What is amniocentesis?
- From 15 - 20 weeks (mean 16 weeks in Vic), if you do it too early get limb deformity
- 20ml amniotic fluid (200mls at 16 weeks/35mls 10wks)
- test may take 2-3 weeks
- spontaneous abortion rate at this stage 3.2% amniocentesis increases the risk 0.3%
- recommended for females >37yrs (if other parameters indicate issues)
Why is the age of a mother a risk factor?
-aneuploidy (+/- chromosomes) in oocytes is more likely as the mother ages
What is the incidence of Trisomy 21 with maternal age?
-the older the mother the greater the risk of trisomy 21
What is the mean age of parents and what are the trends?
- The median age of all mothers for births registered in 2013 was 30.8 years, while the median age of fathers was 33.0 years
- The median age of first-time mothers in 2013 was 29.3 years, 63% of whom were married at the time of giving birth.
- the age of first time mothers is rising, it used to be 25.4 in 1986
What does normal meiosis in a female gamete look like?
-
How does an aneuploidy result from a non-disjunction at anaphase I?
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How does an aneuploidy result from a non-disjunction at anaphase II?
-
How can an aneuploidy result from a non-disjunction at anaphase I/II when the sex chromosomes are in play?
- if have non-disjuntcion in the mother so have 2 XX, and then get an Y from the father get Klinfelter syndrome XXY
- if XXX then fine-ish, maybe reproductive problems
What is this?
- XXY, XXX or XO, no viable offspring if YO
- need an X to survive
- Turner syndrome (XO)
What are the signs used in pedigrees?
-
What are examples of autosomal recessive disorders?
- Thalassaemia
- Albinism
- Phenylketonuia
- Tay Sachs
- Cystic Fibrosis (the pedigree indicates it is an autosomal recessive disorder as the daughter has it but the father doesn’t )
What are example of X-linked recessive inheritance?
- Haemophilia
- Colour blidness
- you cannot survive without and X, you can make without Y in some cases
- higher proportion of males with the trait if it is X linked
- and if a daughter has it then the father has to have it since she had to have gotten it from the father’s X
Why is this not X linked pattern of inheritance?
-XaXa cannot happen from these parents (if father is carrying a trait then the daughter has to have it)
What does reduced penetrance mean and what is the pattern of inheritance in these cases?
- some individuals fail to express the trait, even though they carry the allele
- this is the case in rare human disorders
- e.g. reduced penetrance in this pedigree as II-I must have the mutation but not show it
What is the concept of lethality and how does this affect the phenotype?
- a mutation in one gene with a lethal genotype
- eg.: • Achondroplasia, autosomal dominant dwarfism
- Gene is FGFR3
- Mutations interrupt chondrocyte
- production -> shortening of long bones
- e.g. achondroplasia, AA individual dies in utero, Aa survives and shows dwarfism (often a de novo mutation)
- Alleles that cause an organism to die only when present in homozygous condition are called lethal alleles.
- If the mutation is caused by a dominant lethal genotype, the heterozygote for the allele will show the lethal phenotype, the homozygote dominant is impossible. If the mutation is caused by a recessive lethal genotype, the homozygote for the allele will have the lethal phenotype.
What is the concept of variable expression?
- eg. Neurofibramatosis NF1, different people will have different severity of the tumours
- occurs when a phenotype is expressed to a different degree among individuals with the same genotype.For example, individuals with the same allele for a gene involved in a quantitative trait like body height might have large variance (some are taller than others)
- same genotype but expressed differently in individuals -it interacts with other genes in the genome
What is the inheritance pattern of polydactyly?
-reduced penetrance, also variable expression
What is an example of a single gene with multiple mutations causing a disorder?
- Cystic Fibrosis over 2000 mutations in the CFTR gene locus 7q31.2 that cause the disease
- Most common mutation is F508delta. A deletion of 3 bases making up the codon for phenylalanine (the 508th amino acid) of the CFTR protein
- only 127/2000 mutation result in defective protein
- the frequency of the mutation heavily depends on your ethnic origin
What diseases are caused by dynamic mutations?
- the expression and occurrence depends on the repeats
- e.g.spinal cerebellar ataxis, Huntington’s , muscular dystrohy
- dynamic, can expand
- in Hungtiong’s it is in the coding part of the gene
- in the Fragile X it is in the promoter and stops expression of FMR1 gene= no protein causing defect, triplet repeat that can expand during transmission
- in Huntington’s = toxic protein causes defects
What is the pattern of multifactorial inheritance?
- there are factors other than the DNA itself that determines the occurrence of the defect
- have to reach a “threshold” and then have the defect
- e.g: • Spina bifida and anencephaly - genetic and environmental
- What environmental factors influence expression?
- Females in early pregnancy take folic acid
- eg.: Genes eg., BRCA1, BRCA2, p53, RB1 all known to be involved in certain cancers but Environmental factors too.
- this is what is involved in the risk factors for eg. cancer etc.
What is mitochondrial inheritance like?
-Some affect a single organ, such as the eye in Leber hereditary optic neuropathy (LHON), but many involve multiple organ systems. Many affected individuals display a cluster of clinical features such as ‘mitochondrial encephalopathy with lactic acidosis and stroke-like episodes’ (MELAS), or myoclonic epilepsy with ragged-red fibres (MERRF)
