Genetics

Question 1

What is CVS?

Answer 1

involves an ultrasound guided biopsy of the placental tissue, it is used when testing is done earlier in pregnancy (before 15 weeks)

Question 2

What is amniocentesis?

Answer 2

involves ultrasound guided aspiration of some amniotic fluid using a needle and syringe, only performed later in pregnancy once there is enough amniotic fluid to make it safer to take a test.

Question 3

What is non-invasive prenatal testing?

Answer 3

• Uses free foetal DNA in maternal circulation
• Currently used for sex determination and trisomy testing

Question 4

When can CVS be done?

Answer 4

11.5 weeks

Question 5

When can amniocentesis be done?

Answer 5

15+ weeks

Question 6

How can NIPT give false negatives?

Answer 6

due to inadequate foetal fraction

Question 7

How can NIPT give false positives?

Answer 7

due to confined placental mosaicism or maternal malignancy

Question 8

How can NIPT help with diagnosis of Down Syndrome?

Answer 8

If there is a bit more chromosome 21 than you would expect, the pregnancy is at high risk (99%) of trisomy 21, if not pregnancy is at low risk.

Question 9

What are the advantages of NIPT?

Answer 9

Allows us to do fewer invasive tests
Non-invasive so no risk of miscarriage

Question 10

What is the termination option before 13 weeks?

Answer 10

Surgical termination

Question 11

What is the termination option after 13 weeks?

Answer 11

Induction

Question 12

Is there a time limit on termination of pregnancy?

Answer 12

No time limit on TOP if there is a risk of serious abnormality in the child or to the health of the mother

Question 13

Why is a TOP a personal decision?

Answer 13

• Social and religious views
• Previous experience
• Perception of disease

Question 14

How does knowing a diagnosis of Haemophilia in an unborn baby influence management?

Answer 14

May change delivery plan to avoid forceps etc and may go for an elective section.

Question 15

What are the indications for invasive testing?

Answer 15

• High risk of chromosomal trisomy on screening (NIPT)
• Foetal abnormality on scanning
  
  • Small size, especially if symmetrical growth failure
  • Increased nuchal thickness
  • Structural malformation e.g., brain or heart
• Parent has balanced chromosomal rearrangement

Question 16

What are the advantages of invasive testing?

Answer 16

• High resolution
• Technically easier
• Rapid

Question 17

What are the disadvantages of invasive testing?

Answer 17

• Also finds polymorphisms (SNPs or CNVs) so may make incidental findings
• 1/100 risk of miscarriage for both CVS and amniocentesis

Question 18

What are the 2 methods of genetic testing?

Answer 18

Array-CGH -> Allows you to look for sub-microscopic deletions or duplications of chromosome material across the whole human genome. Only detects chromosome imbalance
Next Generation Sequencing - finds small sequence changes

Question 19

What is a nonsense mutation?

Answer 19

mutated codon is a premature stop codon

Question 20

What is a missense mutation?

Answer 20

mutated codon codes for a different amino acid

Question 21

What is a silent mutation?

Answer 21

mutated codon codes for same amino acid

Question 22

What is a frameshift mutation?

Answer 22

occur when the addition or deletion of a base alters the reading frame of the gene

Question 23

What is a triplet expansion?

Answer 23

triplet is repeated

Question 24

What is autosomal dominant inheritance?

Answer 24

only one copy of a disease allele is necessary for an individual to be susceptible to expressing the phenotype

Question 25

What is autosomal recessive inheritance?

Answer 25

two copies of a disease allele are required for an individual to be susceptible to expressing the phenotype

Question 26

What is x-linked dominant inheritance?

Answer 26

only one copy of a disease allele on the X chromosome is required for an individual to be susceptible to an X-linked dominant disease, males and females can be affected but males more severely affected as they only have one X chromosome.

Question 27

What is x-linked recessive inheritance?

Answer 27

two copies of a disease allele on the X chromosome are required for an individual with two X chromosomes (females) to be affected with an X-linked recessive disease

Question 28

What is de-novo dominant inheritance?

Answer 28

occurs when a de-novo variant in one copy of a gene is sufficient to result in a clinical phenotype. A significant proportion of severe neonatal presentations are de-novo genetic

Question 29

When would we do newborn DNA sequencing?

Answer 29

if infant presents with a phenotype indicative of a genetic disorder, NGS can be used to test a differential after other testing e.g., family history, neurology finding, scan findings

Question 30

What is filtering and how does it work?

Answer 30

• Used to find the mutation that matters
  1. 3,000,000 genetic variants → exclude variants known to be a polymorphism
  2. 1000s of genetic variants → keep variants known to affect gene function
  3. 100s of genetic variants → does the gene explain the phenotype?
  4. Hopefully should leave 1 mutation which is the causative mutation

Question 31

What is trio exome sequencing?

Answer 31

• NGS used to sequence the exome (coding regions) of the DNA of mother, father and baby
• Used as a first line test for acutely unwell children with a likely monogenetic disorder
• Diagnostic rate of 20-40% where there is no clear environmental cause and up to 70% for a child with an abnormal neurological presentation.

Question 32

How do we genetic test in children?

Answer 32

• First identify phenotype - dysmorphology database and other resources can help
• Use aCGH to look for chromosomal imbalance
• Use NGS to look for smaller mutations - requires filtering as above