2 - Prenatal & Newborn Screening Flashcards
Define Congenital Anomalies
structural or functional anomalies that occur during intrauterine env. Congenital = before birth
Give examples of structural birth defect
Cleft lip or cleft palate; heart defects; abnormal limbs
What are the 4 types of Functional or developmental defects and give examples for each?
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
What are the 4 types of base mutation - point substitution and which type of cells do they occur in?
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)
Define frameshift base mutations
Frameshift: addition or deletion of one or more bases, all codons downstream are out of phase leading to different translation and incorrect a.a.
How is sickle cell caused?
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
How is cystic fibrosis caused?
Frameshift
ΔF508, is a deletion (Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F)
Describe Trinucleotide / triplet repeats and what is its inheritance?
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
Define Aneuploidy and what are the 2 types of nondisjunction?
Aneuploidy: abnormal number of chromosomes in cell (45 or 47)
only in gametes (meiosis) so sex linked
First division vs second division
What are the 3 ways gene control can be altered?
Positional effects
Gene enhancing
Gene silencing
Give an example of a condition for positional effect and how is it caused?
Duchenne muscular dystrophy
translocation between one X and an autosome
Give an example of an autosomal aneuploidy and Sex-linked aneuploidy
Trisomy 21: Down’s
Turner’s: 45X0
Give an example of recessive and dominant sex-linked abnormalities
R: Haemophilia and Duchenne muscular dystrophy
D: Rett syndrome
Why do we do prenatal screening?
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
What are some foetal abnormalities that we screen for?
Infection - Hepatitis B, HIV, Syphilis
Alloantibodies - Haemolytic disease of the newborn
Sickle cell and thalassaemia
Down’s
Name few methods of prenatal diagnosis
Amniocentesis
Chorionic villus sampling
Foetal blood sampling
Ultrasound scanning - structural abnormalities
Nuchal translucency - indicative of aneuploidy
What does PAPPA-A stands for?
Pregnancy associated plasma protein- A
What does AFP stands for?
Alpha feto protein
What are some screening tests performed during the first trimester (11-13 weeks)?
Combined test: nuchal translucency, PAPPA-A, ℬ-HCG
sensitivity 85-90%, false positive rate 5%
What are some screening tests performed during the second trimester(18-22 weeks)?
Quad test: ℬ-HCG, AFP, Oestriol, Inhibin-A
sensitivity 81%, false positive rate 5
What does NIPT stands for?
Non-invasive prenatal testing
99% sensitivity; false positive rate 1%
What are some of the factors that should be considered while screening for the maternal markers?
Maternal age; gestational age; weight; smoker; twins; race; diabetes; IVF
Name the 4 conditions where newborn blood spot screening is performed?
- Sickle cell disease
- cystic fibrosis
- congenital hypothyroidism
- inherited metabolic diseases
Give few examples for inherited metabolic disorders
Phenylketonurea (PKU)
Maple syrup disease (MSUD)
Isovaleric acidamia (IVA)
Why screen for these 4 types of conditions (in particular)?
- 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
a) What causes congenital hypothyroidism and what treatment is available?
b) what happens is left untreated?
a)caused by deficiency of thyroxine. Early treatment (less than 21 days) - with thyroxine b) severe, permanent mental and physical disability
What causes PKU?
> 400 mutations of the PAH gene; deficiency of phenylalanine hydroxylase, accumilation of phenylalanine, and deficiency of tyrosine
a) Treatment for PKU
b) What happens if PKU is left untreated?
a) Restrict phenylalanine from diet
b) severe brain damage with mental retardation and seizures
Why are newborns difficult to screen?
- 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 - May have a different biological age (if born before the normal gestational period)
Name a few complications of prematurity and what causes it?
1) anaemia - ioron deficiency, repeated venepunctures
2) infections - invasive treatments, low Igs
3) high sodium - dehydration
4) jaundice - liver immaturity
What causes high/low sodium levels in premature infants?
high sodium - dehydration
low sodium - renal tubule immaturity
What are the alternate sample specimen considerations in neonates?
Dry blood spots, urine, faeces, sweat
Why are alternate sample specimens considered in newborns?
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
Future of prenatal screening…….
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
Full form of PIGD
pre-implanatation genetic diagnosis
