Prenatal diagnosis for Joubert syndrome: Challenges and Possibilities

1. Prenatal diagnosis for Joubert syndrome:Challenges and Possibilities Ian A. Glass, MB ChB, MD, FACMG Associate Professor of Pediatrics and Medicine

2. Prenatal Diagnosis (PND)Topics for this seminar Goals of PND in general Methods of PND PND in Joubert syndrome Strengths/weaknesses of PND for JS Future directions for PND of JS

3. Goals of PND Facilitate informed reproductive choices Reduce anxiety in high-risk groups Enable prenatal treatment, if available Ensure the birth of unaffected infants (termination of affected fetus) Enable preparations for the birth of an affected child Medical care Psychological preparations

4. Indications for PND Screening of high risk groups Advanced Maternal Age (AMA) Particular ethnic groups Cystic fibrosis in Caucasians Sickle cell anemia in African-Americans Specific prenatal testing Family history of prior affected child Muscular dystrophy Joubert syndrome

5. Reproductive options for couples who have a child with JS • Accept the risk without PND • Accept the risk and consider PND imaging: • To be prepared for an affected child • To terminate an affected fetus • Sperm or egg donor to reduce risk • Choose to adopt • Choose not to have additional children ALL of these choices are valid!

6. Methods of PND Non-invasive testing serum markers imaging by ultrasound, fetal-MRI Invasive testing amniocentesis chorionic villus sampling (CVS)

7. Non-invasive testing: Imaging Ultrasound (US) Fetal MRI Screening for high risk groups (e.g. AMA) Directed diagnostic imaging for: Fetuses with abnormalities Family history of birth defect Post-natal correlations to confirm PND prediction Postnatal follow-up exam and/or testing Fetal autopsy if demise or termination Correlations often not performed !!!

8. Normal Fetal Hand:3D US

9. Polydactyly:3D US

10. Normal Face:2D and 3D US

11. Non-invasive testing: Imaging Prenatal Hydrocephaluson US

12. Imaging: Post-natal correlation Hydrocephalus on MRI after birth

13. Invasive testing: Amniocentesis • TestRisk of Loss Timing Result • Amniocentesis 1/200 16 wk 18-22wk

14. Invasive testing: Chorionic villus sampling • TestRisk of Loss Timing Result • CVS 1/100 11 wk 11-12wk

15. PND in Joubert syndrome

16. The flow of genetic information: Chromosomes  Genes (DNA)  Message (RNA) Protein Gene made of DNA Nucleus Cell Chromosomes RNA Protein Testing Opportunities

17. Family with a child with JS ? RR = 25% What prenatal testing is available? Diagnosis: JS + MTS

18. Methods for PND in JS Invasive testing Useful for JS? amniocentesis Maybe* chorionic villus sampling (CVS) Maybe* Non-invasive testing serum markers (triple screen, AFP) No imaging by ultrasound, fetal-MRI YES Most of these methods are not useful because chromosomal, DNA* and protein markers for JS are not available *If a known mutation in a JS gene

19. Is DNA testing currently available for JS? Best situation: one gene causes all JS cases But we have at least 5 JS genes known/mapped already Goal: direct DNA testing once JS genes are known 2006: Only two direct DNA tests are clinically “available” for JS for the NPHP1 and AHI1 genes,accounting for <15% of JS Specific gene testing may be indicated if an older sibling has a mutation in a known JS gene

20. What is available now? • Prenatal imaging by ultrasound scanning (considerable experience) • Prenatal imaging by fetal MRI scanning (increasing experience)

21. PND of JSFamily History is Key

22. Molar Tooth Sign deep interpeduncular fossa thick, elongated SCPs cerebellar vermis hypoplasia

23. Cerebellar vermis in utero Normal Normal Hypoplastic

24. JS in utero: absence of cerebellar vermis Ultrasound MRI

25. JS: enlarged cisterna magna Ultrasound MRI

26. JS in utero:polydactyly 2 3 1 4 5 6 Aslan et al. 2002

27. JS in utero:encephalocele Wang et al. 1999

28. US for PND: promise and perils • Advantages: • Non-invasive • Can see important structures: brain, fingers, kidneys • Can be repeated throughout pregnancy • Relatively inexpensive • Standardized measurements • Disadvantages: • Technician-dependent: angle of transducer • Observer-dependent: experience in looking at brain • May not see subtle abnormalities • Timing is crucial: defects may not be visible early

29. For couples who desire prenatal imaging • 11-12 wks: baseline US for dates, nuchal fold • 16 wks: US for cranial views, skull, fingers, kidney • 18 wks: US to confirm cerebellar growth • 20-22 wks: US for above + fetal MRI • Further imaging, dependent on prior findings • If possible, review by an experienced radiologist, or perinatologist in evaluations of the posterior fossa

30. Improving PND of JS • Systematic review of prenatal imaging • Correlation with outcomes • Follow ongoing pregnancies with imaging studies • Hypothesis: Systematic review of ultrasound and/or fetal MRI imaging will improve diagnosis of JS and generate guidelines for prenatal monitoring of at-risk pregnancies

31. JS PND Summary • Can we diagnose JS prenatally given a prior family history? • Sometimes, but the reliability is unknown • Can we diagnose JS prenatally without a prior family history? • Almost never, if at all • Improved PND is needed, imaging is our best option at this time

32. Making an informed choice • A Genetic Counselor or Geneticist can help • Discuss options • Provide resources and support • When possible, get information prior to getting pregnant (preconception counseling) • www.genetests.org or www.nsgc.org for a list of local genetic counselors

33. Current Research Efforts • Linkage and other methods to locate new genes • Structural and functional MRI imaging • Improved clinical understanding (JSF Registry, Biobank) • Accurate prenatal diagnosis • Recommendations for medical management

34. How to participate in Joubert research • Contact us: • Dana Knutzen, MS, GC and Melissa Parisi, MD, PhD knutzd@u.washington.edu mparisi@u.washington.edu 800-246-6312, 206-987-3832 • Ian A. Glass, MD and Dan Doherty, MD, PhD ian.glass@seattlechildrens.org dan.doherty@seattlechildrens.org 206-987-5142 206-987-2489

35. Acknowledgments Research Collaborators • William Dobyns, MD • Joseph Gleeson, MD • Friedhelm Hildebrandt, MD • Bernard Maria, MD • David Nyberg, MD • Hamit Ozyurek, MD • Joseph Pinter, MD • Dennis Shaw, MD • Other collaborators! UW Joubert Center • Phillip Chance, MD • Jon Adkins, BS • Craig Bennett, PhD • Daniel Doherty, MD, PhD • Ian Glass, MD • Nick Gorden, BS • Dana Knutzen, MS You! Children with JSRD and their Families JSF & RCD