Prenatal diagnosis for joubert syndrome challenges and possibilities
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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

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Prenatal diagnosis for joubert syndrome challenges and possibilities l.jpg

Prenatal diagnosis for Joubert syndrome:Challenges and Possibilities

Ian A. Glass, MB ChB, MD, FACMG

Associate Professor of Pediatrics and Medicine

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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

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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

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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

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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!

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Methods of PND

Non-invasive testing

serum markers

imaging by ultrasound, fetal-MRI

Invasive testing


chorionic villus sampling (CVS)

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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 !!!

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Normal Face:2D and 3D US

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Non-invasive testing: Imaging

Prenatal Hydrocephaluson US

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Imaging: Post-natal correlation

Hydrocephalus on MRI after birth

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Invasive testing: Amniocentesis

  • TestRisk of Loss Timing Result

    • Amniocentesis 1/200 16 wk 18-22wk

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Invasive testing: Chorionic villus sampling

  • TestRisk of Loss Timing Result

    • CVS 1/100 11 wk 11-12wk

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The flow of genetic information: Chromosomes  Genes (DNA)  Message (RNA) Protein

Gene made of DNA






Testing Opportunities

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Family with a child with JS


RR = 25%

What prenatal testing

is available?

Diagnosis: JS


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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

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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

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What is available now?

  • Prenatal imaging by ultrasound scanning (considerable experience)

  • Prenatal imaging by fetal MRI scanning (increasing experience)

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PND of JSFamily History is Key

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Molar Tooth Sign

deep interpeduncular fossa

thick, elongated SCPs

cerebellar vermis hypoplasia

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Cerebellar vermis in utero




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JS in utero: absence of cerebellar vermis



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JS in utero:polydactyly







Aslan et al. 2002

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JS in utero:encephalocele

Wang et al. 1999

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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

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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

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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

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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

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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)

  • or for a list of local genetic counselors

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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

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How to participate in Joubert research

  • Contact us:

    • Dana Knutzen, MS, GC and Melissa Parisi, MD, PhD

      800-246-6312, 206-987-3832

    • Ian A. Glass, MD and Dan Doherty, MD, PhD



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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