7. Newborn screening

Question 1

What are the 6 WHO criteria for disease screened for in newborns?

Answer 1

1. Known incidence in population
2. Associated with significant morbidity / mortality
3. Clinically & biochemically well-defined
4. Effective treatment available
5. Period before onset when intervention improves outcome
6. Safe, simple, robust, cost-effective screening test

Question 2

What challenges are associated with using genetics for NBS?

Answer 2

No phenotype therefore interpretation difficult

Potentially many VUSs

Genotypes with variable age of onset/penetrance

Question 3

What are the 9 diseases screened for in newborns in the UK?

Answer 3

1. Phenylketonuria
2. CF
3. Congenital hypothyroidism
4. MCADD
5. Sickle cell
6. Maple syrup urine disease
7. Homocystinuria
8. Glutaria acidaemia 1
9. Isovaleric acidaemia

Question 4

What causes PKU and what is the phenotype?

Answer 4

Deficiency in phenylalanine dehydroxylase enzyme due to PAH mutation

Can’t break down phenylalanine

Profound & irreversible ID at 6 months

Question 5

How is PKU treated?

Answer 5

Low protein diet

Sapropterin (since 2021) stimulates residual
phenylalanine hydroxylase activity

Question 6

How is PKU screened for in newborns?

Answer 6

Tandem mass spectrometry for ratio of Phe:Tyr

Question 7

What causes congenital hypothyroidism?

Answer 7

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

Question 8

How is congenital hypothyroidism treated?

Answer 8

Levothyroxine

Question 9

What causes MCADD?

Answer 9

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

Question 10

What is the most common MCADD variant and what is the effect of it?

Answer 10

ACADM Lys304Glu

MCAD protein has 4 monomers, mutations cause tetramer to dissociate –> reduced activity

Question 11

How is MCADD screened for?

Answer 11

Mass spectrometry of octanoylcarnitine (C8), followed by Lys304Glu testing

Question 12

What causes sickle cell disease?

Answer 12

Glu6Val in HBB

Causes deformed RBCs

Question 13

What is the effect of deformed RBCs caused by sickle cell?

Answer 13

Vaso-occlusive events (RBCs clock blood flow, tissue derived of oxygen) - acute, chronic pain and organ damage

Chronic hemolytic anemia

Question 14

How is SCD screened for in newborns?

Answer 14

HPLC, isoelectric focussing, tandem mass spec

Question 15

How is CF screened for?

Answer 15

Immunoreactive trypsinogen –> CF4 if IRT >99.5th centile

No mutations on CF4 –> repeat IRT

CFEU2 if 1 mutation on CF4

Question 16

Why is it important to combine IRT and genetics in NBS for CF?

Answer 16

Due to poor positive predictive value of IRT alone, especially in first few days of life

Question 17

What is the common feature of maple syrup urine disease, isovaleric acidaemia, glutaric acidaemia and homocystinuria?

Answer 17

All inborn errors of metabolism that result in an inability to metabolise certain amino acids

Accumulation of amino acids leads to toxicity

Question 18

What is the Generation Study?

Answer 18

Researsch study to sequence genomes of 100,000 newborns

Collaboration between Genomics England and NHS

Question 19

What are the 4 principles that must be met for a disorder to be included in the Generation Study?

Answer 19

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

Question 20

How many conditions/genes are tested for in the Generation Genomes study?

Answer 20

> 200 disorders, >500 genes but only known disease causing variants

VUSs not screened for to minimise number of false positives

Question 21

What stage is WGS newborn screening at?

Answer 21

Large scale research studies

Essential to generate the data needed for a vigorous evaluation of pros and cons

Question 22

What are the negatives of newborn WGS?

Answer 22

1. Cost associated with:

a) Substantial investment needed to create the informatics infrastructure needed to manage the volume & complexity of data

b) Workforce capacity

2. Need for informed consent - understanding of what the programme entails and how children will make their own choices
3. Risk of raising unjustified anxiety around healthy babies

Question 23

What are the benefits of newborn WGS?

Answer 23

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

Question 24

What are the 3 aims of the Genome Study?

Answer 24

1. Early identification & treatment of rare conditions
2. Enable research
3. Explore risks & benefits of storing an individual’s genome over their lifetime