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Prenatal diagnosis for Joubert syndrome: Challenges and Possibilities Ian A. Glass, MB ChB, MD, FACMG Associate Professor of Pediatrics and Medicine 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 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 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 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! Methods of PND • Non-invasive testing • serum markers • imaging by ultrasound, fetal-MRI • Invasive testing • amniocentesis • chorionic villus sampling (CVS) 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 !!! Normal Fetal Hand: 3D US Polydactyly: 3D US Normal Face: 2D and 3D US Non-invasive testing: Imaging Prenatal Hydrocephalus on US Imaging: Post-natal correlation Hydrocephalus on MRI after birth Invasive testing: Amniocentesis Test • Amniocentesis Risk of Loss 1/200 Timing Result 16 wk 18-22wk Invasive testing: Chorionic villus sampling Test • CVS Risk of Loss 1/100 Timing Result 11 wk 11-12wk PND in Joubert syndrome The flow of genetic information: Chromosomes Genes (DNA) Message (RNA) Protein Gene made of DNA Cell Nucleus Chromosomes RNA Protein Testing Opportunities Family with a child with JS ? Diagnosis: JS + MTS RR = 25% What prenatal testing is available? Methods for PND in JS • Invasive testing Useful for JS? • amniocentesis • chorionic villus sampling (CVS) Maybe* Maybe* • Non-invasive testing • serum markers (triple screen, AFP) • imaging by ultrasound, fetal-MRI No 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 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 What is available now? • Prenatal imaging by ultrasound scanning (considerable experience) • Prenatal imaging by fetal MRI scanning (increasing experience) PND of JS Family History is Key Characteristic MTS Small vermis /large cisterna magna Hypotonia Ataxia Abnormal Eye Movements Developmental Delay Irregular breathing pattern Polydactyly Encephalocele Abnormal kidneys Postnatal Prenatal + + ? +/- + + + + + + + + +/+ + +/- Molar Tooth Sign deep interpeduncular fossa thick, elongated SCPs cerebellar vermis hypoplasia Cerebellar vermis in utero Normal Normal Hypoplastic JS in utero: absence of cerebellar vermis Ultrasound MRI JS: enlarged cisterna magna Ultrasound MRI JS in utero: polydactyly 3 2 4 1 5 6 Aslan et al. 2002 JS in utero: encephalocele Wang et al. 1999 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 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 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 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 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 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 How to participate in Joubert research • Contact us: – Dana Knutzen, MS, GC and Melissa Parisi, MD, PhD [email protected] [email protected] 800-246-6312, 206-987-3832 – Ian A. Glass, MD and Dan Doherty, MD, PhD [email protected] [email protected] 206-987-5142 206-987-2489 Acknowledgments 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 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! You! Children with JSRD and their Families JSF & RCD