7. Newborn screening Flashcards
What are the 6 WHO criteria for disease screened for in newborns?
- Known incidence in population
- Associated with significant morbidity / mortality
- Clinically & biochemically well-defined
- Effective treatment available
- Period before onset when intervention improves outcome
- Safe, simple, robust, cost-effective screening test
What challenges are associated with using genetics for NBS?
No phenotype therefore interpretation difficult
Potentially many VUSs
Genotypes with variable age of onset/penetrance
What are the 9 diseases screened for in newborns in the UK?
- Phenylketonuria
- CF
- Congenital hypothyroidism
- MCADD
- Sickle cell
- Maple syrup urine disease
- Homocystinuria
- Glutaria acidaemia 1
- Isovaleric acidaemia
What causes PKU and what is the phenotype?
Deficiency in phenylalanine dehydroxylase enzyme due to PAH mutation
Can’t break down phenylalanine
Profound & irreversible ID at 6 months
How is PKU treated?
Low protein diet
Sapropterin (since 2021) stimulates residual
phenylalanine hydroxylase activity
How is PKU screened for in newborns?
Tandem mass spectrometry for ratio of Phe:Tyr
What causes congenital hypothyroidism?
Thyroid fails to produce thyroxine due to absence/abnormal development of thyroid or lack of TSH
Causes failure to grow properly, permanent physical and mental disability
How is congenital hypothyroidism treated?
Levothyroxine
What causes MCADD?
Inability to metabolise fats –> build up of medium chain fatty acids in particular octanoylcarnitine (C8)
Prevents body from using fats properly as part of glucose homeostasis - particularly important in early infancy
What is the most common MCADD variant and what is the effect of it?
ACADM Lys304Glu
MCAD protein has 4 monomers, mutations cause tetramer to dissociate –> reduced activity
How is MCADD screened for?
Mass spectrometry of octanoylcarnitine (C8), followed by Lys304Glu testing
What causes sickle cell disease?
Glu6Val in HBB
Causes deformed RBCs
What is the effect of deformed RBCs caused by sickle cell?
Vaso-occlusive events (RBCs clock blood flow, tissue derived of oxygen) - acute, chronic pain and organ damage
Chronic hemolytic anemia
How is SCD screened for in newborns?
HPLC, isoelectric focussing, tandem mass spec
How is CF screened for?
Immunoreactive trypsinogen –> CF4 if IRT >99.5th centile
No mutations on CF4 –> repeat IRT
CFEU2 if 1 mutation on CF4
Why is it important to combine IRT and genetics in NBS for CF?
Due to poor positive predictive value of IRT alone, especially in first few days of life
What is the common feature of maple syrup urine disease, isovaleric acidaemia, glutaric acidaemia and homocystinuria?
All inborn errors of metabolism that result in an inability to metabolise certain amino acids
Accumulation of amino acids leads to toxicity
What is the Generation Study?
Researsch study to sequence genomes of 100,000 newborns
Collaboration between Genomics England and NHS
What are the 4 principles that must be met for a disorder to be included in the Generation Study?
A. Strong evidence that genetic variants cause the disease & can be reliably detected. Confirmatory testing available
B. High penetrance disorders - high proportion of individuals with variant(s) have symptoms that have a debilitating
impact on quality of life if left undiagnosed
C. Early/pre-symptomatic treatment has substantially
improved outcomes
D. Interventions are equitably accessible for all through the NHS
How many conditions/genes are tested for in the Generation Genomes study?
> 200 disorders, >500 genes but only known disease causing variants
VUSs not screened for to minimise number of false positives
What stage is WGS newborn screening at?
Large scale research studies
Essential to generate the data needed for a vigorous evaluation of pros and cons
What are the negatives of newborn WGS?
- Cost associated with:
a) Substantial investment needed to create the informatics infrastructure needed to manage the volume & complexity of data
b) Workforce capacity
- Need for informed consent - understanding of what the programme entails and how children will make their own choices
- Risk of raising unjustified anxiety around healthy babies
What are the benefits of newborn WGS?
Screen for early-onset, severe, treatable conditions to alter lifelong outcomes
Test for all treatable genetic disorders in a single assay - doesn’t matter if most are very rare
Reduces diagnostic odyssey
What are the 3 aims of the Genome Study?
- Early identification & treatment of rare conditions
- Enable research
- Explore risks & benefits of storing an individual’s genome over their lifetime
