1. Detection of heterozygotes
in newborn screening
Amsterdam
ESN:
Vereniging tot bevordering
onderzoek Erfelijke
Stofwisselingsziekten in het Nederlandse taalgebied
Martina Cornel, MD, PhD
Professor of Community Genetics & Public Health Genomics,
Dept Clinical Genetics

2. Autosomal recessive 2 mutations in gene: infant develops disease
Most parents (80-90%) do not know in advance that they are (healthy) carriers
gezond
patiënt
gezonde
drager

3. Newborn screening conditions…
Are often autosomal recessive
Apart from most infants with CHT and some with congenital deafness
So parents turn out to be carriers of PKU, CAH, MCADD, CF, HbP, etc. after diagnosis in infant
As a consequence of NBS: heterozygosity parents
Recurrence risk in each next pregnancy 25%
But sometimes also infants diagnosed as carrier

4. Carrier status information in NBS
Since NBS-NL extended 3 → 17 treatable conditions
Including sickle cell disease
HPLC
Heterozygotes
Relevant for parents
Opt-out of reporting

5. Opting out of carrier status information

6. A HbP carrier identified in NBSAA Aa aa A ? AA a Aa
If child is carrier, at least one of parents is carrier as well. If in the population 1:10 is carrier, the allele frequency is 1:20, and for each next pregnancy the risk of HbP affected infant is 1/4X1/20=1/80.

7. Additional benefits of screening
Is carrier status information a benefit?
Complicating pre-test counseling:
“If the newborn child is a carrier, then it follows that one, or both, parents (and possibly other children) are carriers. The parents should be alerted to these possible outcomes prior to screening. Information of this kind can, in practice, give rise to misunderstandings with regard to the health of the carriers. etc”
“One problem lies in the fact that it is not always possible to determine for certain whether only one parent is a carrier (as is the case with, for example, cystic fibrosis, where not all mutations are known).”
Health Council of the Netherlands 2005

8. Report CF carrier information from NBS?
Relevant for some parents in connection with future family planning
Secondary finding rather than objective
CF is a severe disorder – if requested, it would be necessary to provide genetic advice and treatment options.
Certainly, parents must be able to make an informed and conscious choice and the consent of parents is required for the provision of information on being a carrier.
Health Council of the Netherlands 2010

9. Sir Muir Gray (Nat Scr Comm UK)
All screening programmes do harm. Some do good as well and, of these, some do more good than harm at reasonable cost.

10. Pros and cons need to be evaluated
Live longer & healthier
False positives
Uncertainty
Carriers (heterozygotes)

11. New technological possibilities
Attunement between parties
Achterbergh et al. Health Policy 2007; 83:

12. Neonatal screening for cystic fibrosis?
Health Council report NL 2005:
50-60 patients per year
600 infants referred for sweat test
400 heterozygotes diagnosed (carriers of CF)
prognosis improved after screening
Advice to perform Pilot Study: CHOPIN (Cystic fibrosis Heelprick screening in a newbOrn Population In the Netherlands).

13. 4 step procedure after CHOPIN:
IRT-PAP-30 mutation panel-sequencing CF gene
Expected to be reported to parents (per year)
25 infants with cystic fibrosis
excl 4 with earlier diagnosis: meconium ileus
12 carriers (heterozygotes)
Ministry of Health accepted Health Council advice and implementated by 1 May 2011
Step 2: PAP will reduce # carriers

14. Phases of life & genetic screening
Preconceptional
Antenatal
Neonatal
Later in life

15. Carrier screening – when?
Before pregnancy (in preconceptional screening) more reproductive options:
No children (adoption)
Preimplantation genetic diagnosis (embryo selection)
Prenatal diagnosis and termination of affected fetuses
Different partner
Donor gametes (artificial insemination donor sperm)
etc

16. What can we learn for other disorders?
The primary aim of NBS is identification of affected infants
Carriers/heterozygotes are unintended findings
If possible, use laboratory techniques that limit the # of heterozygotes identified in NBS
If heterozygotes are identified (and no preconception screening is available in health care systems), report this relevant information to parents!
Recurrence risk is ¼*allele frequency, so more relevant if disorder is more frequent

17. Thank you!