Genetics

Question 1

how is downs syndrome screened for?

Answer 1

nuchal translucency (skin fold thickness behind neck)

blood serum markers in mother

Question 2

why is the nuchal translucency increased in babies with downs syndrome?

Answer 2

indication that lymphatics are developing too slowly - gap is too large

Question 3

how is invasive genetic testing done whilst the foetus is in utero?

Answer 3

need to test tissue with same genetic makeup as the baby ie chorionic villus sampling of placenta or amniocentesis

Question 4

when can chorionic villus sampling and amniocentesis take place?

Answer 4

CVS - 11.5 weeks

amniocentesis - 15 weeks

Question 5

what is non invasive prenatal testing?

Answer 5

taking mothers blood and testing for free foetal DNA

- this can get into mothers circulation via placenta

Question 6

what can non-invasive prenatal testing look for?

Answer 6

sex of baby
trisomy

occasionally can look for chromosome deletions or single gene transfers

Question 7

what is meant by confined placental mosaicism?

Answer 7

trophoblasts divide quickly - develop more abnormalities than cells that go on to become blastocyst

placenta may have chromosome abnormalities that the baby does not have

Question 8

if NT, serum markers in the mothers blood and NIPT indicate a high risk of trisomy 21, what is the percentage risk of the baby having this condition?

Answer 8

99%+

Question 9

how do geneticists test mothers blood in NIPT and confirm a high suspicion of trisomy 21?

Answer 9

count each number of each chromosome
count number of chromosome 21

*if out of proportion to the number of other chromosomes, this would indicate T21

Question 10

NIPT can also be used for what other genetic conditions?

Answer 10

T18 (edwards)
T12 (patau’s)

also turners 45X and kleinfelters 47XXY

Question 11

what does NIPT reduce the risk of?

Answer 11

miscarriage due to amniocentesis

Question 12

describe the appearance of a baby with downs syndrome?

Answer 12

short fingers
round face
large tongue
epicanthic folds

Question 13

what are the benefits of an antenatal genetic screening test?

Answer 13

identify and treat early

identify if other family members are at risk

Question 14

why is there a debate surrounding screening for downs syndrome in pregnancy?

Answer 14

there is not additional benefit to treating early

however people do say that early termination option for mother may be a benefit to the child

Question 15

up to what gestation can a mother choose to terminate her baby who is at risk of downs syndrome?

Answer 15

no limit - if a risk of serious abnormality to child or to health of mother

Question 16

what is anencephaly, and why is early diagnosis significant?

Answer 16

no brain / head development

baby may progress to full term (may be stillborn due to labour)

parents need to psychologically prepare for appearance and limited survival of baby

Question 17

if a family do not wish to proceed with a termination after a difficult genetic diagnosis in their baby, what other option do they have?

Answer 17

carry baby to term

organ donation

Question 18

how does a baby with T18 (Edward’s) appear and how long do babies with this condition survive?

Answer 18

small baby with small facial features

life limited = many don’t survive for long after birth (virtually none within 1 year)

Question 19

is downs syndrome considered a “severe” genetic disease?

Answer 19

not necessarily due to variable presentation but parents may not be equipped to deal with these

they can have

• cv disease
• behaviour issues
• low IQ requiring lots of support
• multiple surgeries - time in ICU
• increased incidence of some cancers

Question 20

if a US scan indicates a hand abnormality - what must you be aware of?

Answer 20

if this part of another condition / syndrome eg DiGeorge, thrombocytopaenic absent radius etc

Question 21

what criteria do patients make a termination of pregnancy decision upon?

Answer 21

social / religious views
previous experience
perception of disease

Question 22

what is NIPT eventually going to be able to analyse?

Answer 22

chromosome karyotype

Question 23

what invasive genetic testing is carried out on the chorionic villus sample of or an amniocentesis sample?

Answer 23

chromosome (microarray 1st line)

single gene changes

• PCR
• next generation sequencing

Question 24

what is the problem with chromosome microarray?

Answer 24

cannot pick up balanced translocations

- only identifies extra or missing genetic material

Question 25

what can chromosome microarray be used to identify?

Answer 25

trisomy
foetal abnormalities
unbalanced translocations

Question 26

what is the disadvantage of PCR?

Answer 26

you need to know where to look within 30,000 genes
cannot sequence entire genome

eg if baby is thought to display MG symptoms, then this is an NMJ problem and all genes encoding for ACh can be tested

Question 27

prenatal genetic testing allows the obstetrics team to decide on a high or low risk pathway for baby’s delivery - true or false?

Answer 27

true

Question 28

what is meant by a “floppy baby”?

Answer 28

lack of head control 
low tone 
baby lying flat 
no resistance to movement 
easily moved and fall out of grasp

Question 29

where in the nervous system can a lesion cause a floppy baby?

Answer 29

cortex 
spinal cord 
anterior horn cells / motor neurone
NMJ
muscles

Question 30

what problems in a baby’s cortex can cause a floppy baby?

Answer 30

hypoxic ischaemic encephalopathy 
intracranial haemorrhage 
cerebral malformation 
chromosomal (T21, prader-willi)
congenital infection (TORCH)
acquired infection 
peroxisomal disorders
drugs eg benzodiazepines

Question 31

what common congenital infections are outlined by the acronym TORCH?

Answer 31

TO - toxoplasmosis
R - rubella
C - CMV
H - herpes, HIV, hepatitis

Question 32

what damages the spinal cord and can cause a floppy baby?

Answer 32

birth trauma (breech)

syringomyelia (cysts in spinal cord - mermaid looking baby)

Question 33

what conditions due to damage or lesion of the anterior horn cells can cause a baby to appear floppy?

Answer 33

spinal muscular atrophy

Question 34

how would you determine that the cause of floppy baby was central rather than peripheral?

Answer 34

normal strength
normal or increased reflexes
+/- seizures, dysmorphic features or decreased alertness

Question 35

what investigations would you consider if a “floppy baby” was presented?

Answer 35

bloods

• genetic
• metabolic
• congenital infection screen
• creatinine kinase (increases if muscle breakdown)

imaging

• US
• MRI

neuro

• EEG
• EMG (only after 6 months of age)

Question 36

what early intervention can be offered if the disease causing floppy baby is picked up early?

Answer 36

respiratory support (if breathing muscles struggling) 
feeding support 
physio 
OT 
parental involvement

Question 37

if a family history does not highlight a dominant, recessive or X linked pattern of genetic disease, does this mean that a baby’s condition has no genetic cause?

Answer 37

no - may be a de novo mutation

Question 38

why does consanguinity increase recessiveness of genetic disease?

Answer 38

people reproducing are from the same genetic lineage therefore both are more likely to be carriers

Question 39

what disorders can be offered rapid testing after a floppy baby is noticed on examination, yet no abnormalities on chromosome microarray?

Answer 39

myotonic dystrophy
spinal muscular atrophy
prader-willi syndrome

Question 40

what part of the genetic material is sequenced using next generation sequencing?

Answer 40

don’t need to sequence whole genome
only sequence exons (2-3%)
beware of polymorphisms which may not actually cause disease

Question 41

give an example of a condition which can cause floppy baby but can now be treated?

Answer 41

spinal muscular atrophy

• genetic treatment is targeted at RNA to modify damaged mRNA
• NNT = 1 or 2 so very effective
• however, very expensive