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 Goals of PND in general Methods of PND Methods of PND PND in Joubert syndrome PND in Joubert syndrome Strengths/weaknesses of PND for JS Strengths/weaknesses of PND for JS Future directions for PND of JS Future directions for PND of JS

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

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

5. Reproductive options for couples who have a child with JS Accept the risk without PNDAccept the risk without PND Accept the risk and consider PND imaging: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 riskSperm or egg donor to reduce risk Choose to adoptChoose to adopt Choose not to have additional childrenChoose not to have additional children ALL of these choices are valid!

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

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

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

13. Invasive testing: Amniocentesis Test Risk of Loss Timing Result Amniocentesis1/200 16 wk 18-22wk

14. Invasive testing: Chorionic villus sampling Test Risk of Loss Timing Result CVS1/100 11 wk 11-12wk

15. PND in Joubert syndrome

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

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

18. Methods for PND in JS Invasive testing Useful for JS? Invasive testing Useful for JS? amniocentesis Maybe* amniocentesis Maybe* chorionic villus sampling (CVS) Maybe* chorionic villus sampling (CVS) Maybe* Non-invasive testing Non-invasive testing serum markers (triple screen, AFP)No serum markers (triple screen, AFP)No imaging by ultrasound, fetal-MRIYES imaging by ultrasound, fetal-MRIYES 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 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 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 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 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 ultrasound scanning (considerable experience) Prenatal imaging by fetal MRI scanning (increasing experience)Prenatal imaging by fetal MRI scanning (increasing experience)

21. PND of JS Family History is Key CharacteristicPostnatalPrenatal MTS+? Small vermis /large cisterna magna ++/- Hypotonia+- Ataxia+- Abnormal Eye Movements +- Developmental Delay +- Irregular breathing pattern ++/- Polydactyly++ Encephalocele++ Abnormal kidneys ++/-

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

23. Cerebellar vermis in utero Normal Hypoplastic Normal

24. JS in utero: absence of cerebellar vermis UltrasoundMRI

25. JS: enlarged cisterna magna UltrasoundMRI

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

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

28. US for PND: promise and perils Advantages:Advantages: –Non-invasive –Can see important structures: brain, fingers, kidneys –Can be repeated throughout pregnancy –Relatively inexpensive –Standardized measurements Disadvantages: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 For couples who desire prenatal imaging 11-12 wks: baseline US for dates, nuchal fold11-12 wks: baseline US for dates, nuchal fold 16 wks: US for cranial views, skull, fingers, kidney16 wks: US for cranial views, skull, fingers, kidney 18 wks: US to confirm cerebellar growth18 wks: US to confirm cerebellar growth 20-22 wks: US for above + fetal MRI20-22 wks: US for above + fetal MRI Further imaging, dependent on prior findingsFurther imaging, dependent on prior findings If possible, review by an experienced radiologist, or perinatologist in evaluations of the posterior fossaIf possible, review by an experienced radiologist, or perinatologist in evaluations of the posterior fossa

30. Improving PND of JS Systematic review of prenatal imagingSystematic review of prenatal imaging Correlation with outcomesCorrelation with outcomes Follow ongoing pregnancies with imaging studiesFollow 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 pregnanciesHypothesis: 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?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?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 timeImproved PND is needed, imaging is our best option at this time

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

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

34. How to participate in Joubert research Contact us:Contact us: –Dana Knutzen, MS, GC and Melissa Parisi, MD, PhD knutzd@u.washington.edu 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 206-987-5142206-987-2489

35. Acknowledgments UW Joubert Center Phillip Chance, MDPhillip Chance, MD Jon Adkins, BSJon Adkins, BS Craig Bennett, PhDCraig Bennett, PhD Daniel Doherty, MD, PhDDaniel Doherty, MD, PhD Ian Glass, MDIan Glass, MD Nick Gorden, BSNick Gorden, BS Dana Knutzen, MSDana Knutzen, MS Research Collaborators William Dobyns, MDWilliam Dobyns, MD Joseph Gleeson, MDJoseph Gleeson, MD Friedhelm Hildebrandt, MDFriedhelm Hildebrandt, MD Bernard Maria, MDBernard Maria, MD David Nyberg, MDDavid Nyberg, MD Hamit Ozyurek, MDHamit Ozyurek, MD Joseph Pinter, MDJoseph Pinter, MD Dennis Shaw, MDDennis Shaw, MD Other collaborators!Other collaborators! You! Children with JSRD and their Families JSF & RCD