clinical genetics: pregnancy and early childhood

Question 1

what are the types of mutations?

Answer 1

stop (nonsense)
missense
silent
frameshift
triplet expansion

Question 2

what is a stop (nonsense) mutation?

Answer 2

mutated codon is a premature stop codon

Question 3

what is a missense mutation?

Answer 3

mutated codon codes for a different amino acid

Question 4

what is a silent mutation?

Answer 4

mutated codon codes for same amino acid

Question 5

what is a frameshift mutation?

Answer 5

insertion or deletion of a base alters the reading frame of the gene

Question 6

what is triplet expansion?

Answer 6

triplet is repeated

Question 7

what are the modes of inheritance?

Answer 7

autosomal dominant
autosomal recessive
x-linked dominant
x-linked recessive
de-novo dominant

Question 8

what is autosomal dominant?

Answer 8

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

Question 9

what is autosomal recessive?

Answer 9

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

Question 10

what is x-linked dominant?

Answer 10

only one copy of a disease allele on X-linked required for an individual to be susceptible to an X-linked dominant disease
males more likely affected as only have one X chromosome

Question 11

what is x-linked recessive?

Answer 11

two copies of disease allele on X chromosome are required for an individual with two X chromosomes (female) to be affected

Question 12

what is de-novo dominant?

Answer 12

occurs when a de-novo variant in one copy of a gene is sufficient to result in a clinical phenotype

Question 13

which type of genetic mode of inheritance are most of severe neonatal presentations?

Answer 13

de-novo

Question 14

what are methods of genetic testing?

Answer 14

array-CGH (aCGH)
next generation sequencing (NGS)

Question 15

what is array-CGH?

Answer 15

allows to look for sub-microscopic deletions or duplications of chromosome material across the whole human genome

Question 16

what does array-CGH only detect?

Answer 16

chromosomal imbalance

Question 17

what does next gen sequencing find?

Answer 17

small sequence changes

Question 18

what is used for fetal DNA sampling?

Answer 18

non-invasive prenatal testing
invasive testing - aCGH

Question 19

what does NIPT involve?

Answer 19

uses free fetal DNA in material circulation
used for sex determination and trisomy testing

Question 20

what are the advantages of NIPT?

Answer 20

allows fewer invasive tests
non-invasive so no risk of miscarriage

Question 21

what are the disadvantages of NIPT?

Answer 21

false negatives - most commonly due to inadequate fetal fraction
false positives - most commonly due to confined placental mosaicism or maternal malignancy

Question 22

what does invasive testing involve?

Answer 22

uses aCGH
sample taken from placenta (chorionic villus sampling) or from amniotic fluid (amniocentesis)

Question 23

what does chronic villus sampling involve?

Answer 23

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

Question 24

what does amniocentesis involve?

Answer 24

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 sample

Question 25

what are the indications for invasive testing?

Answer 25

high risk of chromosomal trisomy on screening (NIPT) fetal abnormality on scanning parent has balanced chromsomal rearrangement

Question 26

what are the advantages of invasive testing?

Answer 26

high resolution technically easier rapid

Question 27

what are the disadvantages of invasive testing?

Answer 27

finds polymorphisms so may make incidental findings risk of miscarriage for both CVS and amniocentesis

Question 28

when is surgical termination of pregnancy allowed?

Answer 28

before 13 weeks - induction after

Question 29

what is new-born DNA sequencing?

Answer 29

if an 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 etc

Question 30

what is filtering used for?

Answer 30

to find the mutation that matters

Question 31

what is trio exome sequencing?

Answer 31

NGS used to sequence the exome (coding regions) of DNA of mother, father and baby low diagnostic rate when there is no clear environmental cause high diagnostic rate for children with an abnormal neurological presentation

Question 32

what is trio exome sequencing a first line test for?

Answer 32

acutely unwell children with a likely monogenetic disorder

Question 33

what are the steps of genetic testing in children?

Answer 33

1. identify phenotype 2. use aCGH to look for chromosomal imbalance 3. use NGS to look for smaller mutations - requires filtering

Question 34

what is penetrance?

Answer 34

proportion of individuals carrying a particular variant of a gene that also expresses associated phenotype

Question 35

what is complete penetrance?

Answer 35

everyone who inherits the disease will develop some degree of symptoms for it

Question 36

what is reduced penetrance?

Answer 36

less than 100% of individuals carrying a particular genotype express associated traits combo of: - genetic - environmental - lifestyle factors

Question 37

what is non-penetrance?

Answer 37

individuals carrying the genotype don't express any symptoms or signs