2 - Prenatal & Newborn Screening

Question 1

Define Congenital Anomalies

Answer 1

structural or functional anomalies that occur during intrauterine env. Congenital = before birth

Question 2

Give examples of structural birth defect

Answer 2

Cleft lip or cleft palate; heart defects; abnormal limbs

Question 3

What are the 4 types of Functional or developmental defects and give examples for each?

Answer 3

1) Nervous system or brain defects - intellectual and developmental disabilities; behavioral disorders; speech difficulties; seizures
2) Sensory problems - hearing loss or visual problems
3) Metabolic disorders - affects an enzyme; not enough end product; build-up of waste product; abnormal function
4) Degenerative disorders - not obvious at birth, but, steadily get worse; eg, muscular dystrophy, Huntington’s

Question 4

What are the 4 types of base mutation - point substitution and which type of cells do they occur in?

Answer 4

Mis-sense: could alter a single amino acid in the protein (abnormal structure or function)

Non-sense: could create chain terminator codons leading to truncated proteins, or alter the splicing of an exon to intron junction, or occur in the promoter region of the gene altering level of expression

Transition: purine (GA); pyrimidine (TC)

Transversion: purine to pyrimidine

Mutations can affect any cell: somatic versus gamete (somatic mutations can lead to cancer, but, are not inherited; often masked by corresponding dominant allele; or masked by surrounding non-mutant cells in adult tissues)

Question 5

Define frameshift base mutations

Answer 5

Frameshift: addition or deletion of one or more bases, all codons downstream are out of phase leading to different translation and incorrect a.a.

Question 6

How is sickle cell caused?

Answer 6

transversion; one codon from GAG to GTG – changes the 6th a.a. in the beta-globin chain from glutamic acid to valine – hydrophylic to hydrophobic

Question 7

How is cystic fibrosis caused?

Answer 7

Frameshift
ΔF508, is a deletion (Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F)

Question 8

Describe Trinucleotide / triplet repeats and what is its inheritance?

Answer 8

Repeats of 3 nucelotide bases due to slippage or mispairing

Dynamic mutations and anticipation

Healthy individuals - relatively low num of repeats.

Phenotypic expression after repeats reach threshold (lower threshold in coding region repeats)
inherit larger number of repeats - more likely to show phenotypic expression (build up in generations)

Usually show dominant pattern

Question 9

Define Aneuploidy and what are the 2 types of nondisjunction?

Answer 9

Aneuploidy: abnormal number of chromosomes in cell (45 or 47)
only in gametes (meiosis) so sex linked

First division vs second division

Question 10

What are the 3 ways gene control can be altered?

Answer 10

Positional effects
Gene enhancing
Gene silencing

Question 11

Give an example of a condition for positional effect and how is it caused?

Answer 11

Duchenne muscular dystrophy

translocation between one X and an autosome

Question 12

Give an example of an autosomal aneuploidy and Sex-linked aneuploidy

Answer 12

Trisomy 21: Down’s

Turner’s: 45X0

Question 13

Give an example of recessive and dominant sex-linked abnormalities

Answer 13

R: Haemophilia and Duchenne muscular dystrophy

D: Rett syndrome

Question 14

Why do we do prenatal screening?

Answer 14

1) To enable timely intervention before or shortly after birth
2) To give parents a chance to abort (30% of affected fetuses are expected to miscarry anyway)
3) To give parents a chance to prepare emotionally, socially, financially and medically

Question 15

What are some foetal abnormalities that we screen for?

Answer 15

Infection - Hepatitis B, HIV, Syphilis

Alloantibodies - Haemolytic disease of the newborn

Sickle cell and thalassaemia

Down’s

Question 16

Name few methods of prenatal diagnosis

Answer 16

Amniocentesis
Chorionic villus sampling
Foetal blood sampling
Ultrasound scanning - structural abnormalities
Nuchal translucency - indicative of aneuploidy

Question 17

What does PAPPA-A stands for?

Answer 17

Pregnancy associated plasma protein- A

Question 18

What does AFP stands for?

Answer 18

Alpha feto protein

Question 19

What are some screening tests performed during the first trimester (11-13 weeks)?

Answer 19

Combined test: nuchal translucency, PAPPA-A, ℬ-HCG

sensitivity 85-90%, false positive rate 5%

Question 20

What are some screening tests performed during the second trimester(18-22 weeks)?

Answer 20

Quad test: ℬ-HCG, AFP, Oestriol, Inhibin-A

sensitivity 81%, false positive rate 5

Question 21

What does NIPT stands for?

Answer 21

Non-invasive prenatal testing

99% sensitivity; false positive rate 1%

Question 22

What are some of the factors that should be considered while screening for the maternal markers?

Answer 22

Maternal age; gestational age; weight; smoker; twins; race; diabetes; IVF

Question 23

Name the 4 conditions where newborn blood spot screening is performed?

Answer 23

1. Sickle cell disease
2. cystic fibrosis
3. congenital hypothyroidism
4. inherited metabolic diseases

Question 24

Give few examples for inherited metabolic disorders

Answer 24

Phenylketonurea (PKU)
Maple syrup disease (MSUD)
Isovaleric acidamia (IVA)

Question 25

Why screen for these 4 types of conditions (in particular)?

Answer 25

• An important health condition
• Simple and validated screening test is available
• Agreed policy for further diagnostic investigation is available in case of positive screening
• Availability of effective screening
• Cost of finding the disease economically balanced against cost of dealing with medical consequences

Question 26

a) What causes congenital hypothyroidism and what treatment is available?
b) what happens is left untreated?

Answer 26

a)caused by deficiency of thyroxine.
Early treatment (less than 21 days) - with thyroxine
b) severe, permanent mental and physical disability

Question 27

What causes PKU?

Answer 27

> 400 mutations of the PAH gene; deficiency of phenylalanine hydroxylase, accumilation of phenylalanine, and deficiency of tyrosine

Question 28

a) Treatment for PKU

b) What happens if PKU is left untreated?

Answer 28

a) Restrict phenylalanine from diet

b) severe brain damage with mental retardation and seizures

Question 29

Why are newborns difficult to screen?

Answer 29

1. establishing a normal range is difficult - a)Adjustment of the newborn to independent life affects production, metabolism and excretion of many metabolites, hormones and enzymes
   b) Rapid growth and maturation further modify biochemical parameters over the coming weeks
2. May have a different biological age (if born before the normal gestational period)

Question 30

Name a few complications of prematurity and what causes it?

Answer 30

1) anaemia - ioron deficiency, repeated venepunctures
2) infections - invasive treatments, low Igs
3) high sodium - dehydration
4) jaundice - liver immaturity

Question 31

What causes high/low sodium levels in premature infants?

Answer 31

high sodium - dehydration

low sodium - renal tubule immaturity

Question 32

What are the alternate sample specimen considerations in neonates?

Answer 32

Dry blood spots, urine, faeces, sweat

Question 33

Why are alternate sample specimens considered in newborns?

Answer 33

As the blood volume in newborns are very low, term neonates have a blood volume of 275 ml and premature babies have only appx.80 ml of blood volume
Babies have a high level of haematocrit and therir plasma yeild is much lower

Question 34

Future of prenatal screening…….

Answer 34

a) NIPT
b) discovery of epigenitic pathology
c) Predicting multifactoral conditions with some genetic basis
d) genetic identity cards (using microarrays)
e) babies by design and PIGD

Question 35

Full form of PIGD

Answer 35

pre-implanatation genetic diagnosis