Human Genetics 2 Flashcards

Question

Genetic Screening in Newborns | General Principles

Answer 1

- condition screened for should be relatively common - condition should be treatable, with early intervention leading to positive outcomes - test should be accurate

Answer 2

- autosomal recessive condition - frequency of 1 in 15000 in UK - caused by a mutation in phenylalanine hydroxylase - if untreated progressive mental retardation occurs - early diagnosis and implementation of low-phenylalanine diet prevents this

Answer 3

- NHS universal screening of all infants at 5 days old, usually with a heel prick blood test - tests for: - -Phenylketonuria - -Congenital Hypothrodism - -Sickle Cell Disease - -Cystic Fibrosis - -Medium Chain Acyl-CoA Dehydrogenase Deficiency - -Duchenne Muscular Dystrophy - -Homocystinuria - -Tyrosinaemia

Answer 4

- we now have the technology to screen for a wider range of genetic disorders - -is there any point testing with no suitable intervention - -how knowledge of susceptibility to a late onset disease affects patient - -would you want to know - -when would you want to know

Answer 5

- amniocentesis samples amniotic fluid to collect foetal cells for analysis - test done at 14-20 weeks

Answer 6

- chronic villus sampling collects placental cells | - test done at 10-15 weeks

Answer 7

- commonly used for screening chromosomal abnormalities e.g. Down's Syndrome - amniocentesis and chronic villus testing - invasive so there is some risk to the foetus - enables intervention before birth - provides parents with information, should they terminate the pregnancy/make preparations for birth etc.

Answer 8

- associated with IVF - single cell can be removed from a ~4 cell stage blastocyst (early embryo) and genotype the DNA by PCR assay - used to screen alleles for single-gene disorders - also used to check embryos generated by IVF to ensure there are no chromosomal abnormalities - many ethical issues: - -IVF typically generates multiple embryos, what happens to the unwanted ones? - -what traits should parents be allowed to chose?

Answer 9

- born with Diamond Blacktan Anaemia (DBA) which prevents the body from making red blood cells - in the short term DBA can be managed with blood transfusions - can be permanently cured with a bone marrow transplant - his parents and sister did not carry compatible antigens - they selected an embryo from IVF with complimentary antigens, umbilical stem cells were collected and used for transplant - this was in 2003 and they had to fly to the US to do this as permission was refused by the UK HFEA

Answer 10

- born with Fanconi Anaemia, a DNA repair defect causing bone marrow failure - first child in the UK to be cured by a 'saviour sibling' - following IVF, 3 day old embryos were tested for a genetic match - umbilical cord blood and bone marrow used for successful transplant - but Fanconi Anaemia is a general DNA repair disorder, Megan may suffer other consequences in tissues not replaced by bone marrow transplant

Answer 11

- we have to know how a condition develops throughout the life of the affected individuals - in many cases, we lack knowledge of the early stages as they may be asymptomatic, so the affected person isn't medically assessed until symptoms appear

Answer 12

- now we can make transgenic mice that have been genetically engineered to contain defective genes and monitor progress throughout development - but, although mice and humans are both mammals, not all disorders progress in the same way in different species

Answer 13

1) embryonic stem cells derived from the inner cell mass (ICM) of the blastocyst are withdrawn, these cells are pluripotent 2) cells are cultured on a growth medium 3) DNA is delivered into the cells by electroporation, the inserted DNA is made up of sequences from either end of the gene of interest with a resistance gene in the middle. 4) a transgene homologous with a host gene can replace it by homologous recombination 5) select for resistance to obtain only transformed cells 6) inject transformed cells into a recipient embryo ensuring they become part of the inner cell mass 7) implant into surrogate mother

Answer 14

- cells taken from white mouse embryo and engineered - engineered cells injected into blastocysts from black mice - some of the offspring are mostly black, some are mostly white, some are a mixture of black white they are chiameras - chiamera mice are crossed with inbred black mice - if the transgenic cells develop as part of the germline in the chiameras then some gametes carry the wildtype allele and some the transgene - gametes with the wildtype allele will produce black offspring when crossed with the black mouse - gametes with the transgene will produce white offspring that are heterozygous for the wildtype and knocked out allele - white offspring can then be inbred to produce homozygous transgenic offspring

Answer 15

- small polypeptide hormone - regulates adipose tissue formation and is involved in controlling appetite and metabolism - mice in which the leptin gene has been knocked out become grossly obese

Answer 16

-transgenic mice expressing a human Huntingdons disease CAG expansin show abnormal behaviour, ataxia and degeneration

Answer 17

- a number of experimental treatments are being investigated based on providing a wildtype allele to a homozygote with two defective copies of the gene - this requires a sufficient number of cells in the affected organ/tissue to take up and express the gene - for success DNA delivery must be highly efficient

Answer 18

- very effective at attaching to cells and delivering genetic material - viral vectors have been widely used

Answer 19

- adeno-associated viruses (AAV) can deliver wildtype CFTR genes to lung epithelial tissue - AAV are weak, non-pathogenic and only weakly immunogenic - continual doses are required as DNA isn't integrated into host genome, the DNA is only transcribed in the cells

Answer 20

-failure to male both T and B cells of the immune system

Answer 21

- a number of genes can mutate to cause SCID - most common is X-linked SCID or X-SCID caused by a mutation in CD132 gene encoding a common component of interleukin receptors required for cell proliferation and differentiation - the second most common cause us ADA deficiency, adenosinedeaminase is required for dNTP production in lymphocytes - there are many other causal mutations

Answer 22

- bone marrow transplant is the best treatment but is limited by the availability of tissue matched donors - in the case that a transplant is not possible or fails, individuals have to be kept isolated to prevent infection that the immune system would not be able to fight off

Answer 23

- David Vetter had the genotype XY and his wife was XsX - their first son was XsY and died of X-SCID - their second son was also born with X-SCID - they also has a daughter but neither her or the parents were a tissue match - but in 1984 after improvements in unmatched transplantation bone marrow from the sister was transplanted - this was initially successful but the transplanted cells were carrying a virus and the second son also died

Answer 24

1) withdraw bone marrow cells from affected individuals 2) deliver a transgene consisting of a normal version of the affected gene 3) culture bone marrow cells in vitro to select a clone of cells containing and expressing the correct gene 4) return the cells to the patient, after whole body irradiation to kill existing bone marrow cells

Answer 25

- bone marrow cells removed from patient - sequence for CD132 protein is engineered into the RNA genome of a retrovirus - the virus is used to infect bone-marrow cells and delivers its genome - reverse transcriptase converts the viral RNA genome into DNA which is able to integrate into the host cell genome - cells now contain a normal copy of the gene and can be returned to the patient - transgenic cells should then replace the patients lymphocytes with normal cells capable of mounting an immune response

Answer 26

- gene therapy for SCID has been trialled since 1990 - first trials conducted with 2 girls with ADA deficiency, they were given engineered transplants over a 2 year period - they are still alive and continue to retain engineered cells but also require a back up therapy enzyme injection - in 2000, 2 boys with X-SCID treated with retrovirally delivered wildtype CD132 gene, 10 months after treatment they were thriving and 8 more patients were treated - in 2003 2 of the patients died of leukaemia, in each case the integrated transgene had inserted adjacent to a tumour suppressor gene affecting its function - further trials were halted and since then more of the patients have developed leukaemia

Human Genetics 2 Flashcards

(50 cards)