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Detection of heterozygotes in newborn screening Amsterdam Martina Cornel, MD, PhD 18.04.2012 Professor of Community Genetics & Public Health Genomics, ESN: Vereniging tot bevordering onderzoek Erfelijke Stofwisselingsziekten in het Nederlandse taalgebied Dept Clinical Genetics Quality of Care EMGO Institute for Health and Care Research Autosomal recessive • 2 mutations in gene: infant develops disease • Most parents (80-90%) do not know in advance that they are (healthy) carriers 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 Carrier status information in NBS • Since 01.01.2007 NBS-NL extended 3 → 17 treatable conditions • Including sickle cell disease • HPLC • Heterozygotes • Relevant for parents • Opt-out of reporting Opting out of carrier status information A HbP carrier identified in NBS A a A A AA Aa A AA a Aa 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. 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 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 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. Pros and cons need to be evaluated • Live longer & healthier • False positives • Uncertainty • Carriers (heterozygotes) New technological possibilities – Attunement between parties Achterbergh et al. Health Policy 2007; 83: 277-286. 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). 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 Phases of life & genetic screening • Preconceptional • Antenatal • Neonatal • Later in life 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 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 Thank you!