Prenatal diagnosis for Joubert syndrome: Challenges and Possibilities

1
Prenatal diagnosis for Joubert syndromeChallenge
s 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 Hand3D US
9
Polydactyly3D US
10
Normal Face2D 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
• Amniocentesis 1/200 16 wk 18-22wk

14
Invasive testing Chorionic villus sampling

• Test Risk 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 lt15 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
Characteristic Postnatal Prenatal
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
Normal
Hypoplastic
24
JS in utero absence of cerebellar vermis
Ultrasound
MRI
25
JS enlarged cisterna magna
Ultrasound
MRI
26
JS in uteropolydactyly
2
3
1
4
5
6
Aslan et al. 2002
27
JS in uteroencephalocele
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_at_u.washington.edu
• mparisi_at_u.washington.edu
• 800-246-6312, 206-987-3832
• Ian A. Glass, MD and Dan Doherty, MD, PhD
• ian.glass_at_seattlechildrens.org
• dan.doherty_at_seattlechildrens.org
• 206-987-5142
• 206-987-2489

35
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