Prenatal diagnosis pnd in joubert syndrome
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Prenatal diagnosis (PND) in Joubert syndrome. Goals of PND. Provide reassurance/reduce uncertainty Prepare for the birth of an affected child Delivery route Delivery location Emotional preparation Assure the birth of an unaffected child Pregnancy termination

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Prenatal diagnosis (PND) in Joubert syndrome

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Prenatal diagnosis pnd in joubert syndrome

Prenatal diagnosis (PND) in Joubert syndrome


Goals of pnd

Goals of PND

  • Provide reassurance/reduce uncertainty

  • Prepare for the birth of an affected child

    • Delivery route

    • Delivery location

    • Emotional preparation

  • Assure the birth of an unaffected child

    • Pregnancy termination

    • (Preimplantation genetic diagnosis)

  • Allow for prenatal treatment


Js is autosomal recessive

JS is autosomal recessive*

Recurrence risk = 25%


Reproductive options

Reproductive options

  • Accept the risk without PND


Reproductive options1

Reproductive options

  • Accept the risk without PND

  • Accept the risk and consider PND:

    • To prepare for an affected child

    • To terminate an affected pregnancy


Reproductive options2

Reproductive options

  • Accept the risk without PND

  • Accept the risk and consider PND:

    • To prepare for an affected child

    • To terminate an affected pregnancy

  • Sperm or egg donor to reduce risk


Reproductive options3

Reproductive options

  • Accept the risk without PND

  • Accept the risk and consider PND:

    • To prepare for an affected child

    • To terminate an affected pregnancy

  • Sperm or egg donor to reduce risk

  • Choose to adopt


Reproductive options4

Reproductive options

  • Accept the risk without PND

  • Accept the risk and consider PND:

    • To prepare for an affected child

    • To terminate an affected pregnancy

  • Sperm or egg donor to reduce risk

  • Choose to adopt

  • Choose not to have additional children


Reproductive options5

Reproductive options

  • Accept the risk without PND

  • Accept the risk and consider PND:

    • To prepare for an affected child

    • To terminate an affected pregnancy

  • Sperm or egg donor to reduce risk

  • Choose to adopt

  • Choose not to have additional children

ALL of these choices are valid.


Risk scenarios

Risk scenarios

  • Prior affected child: 25% risk each pregnancy

    • Clinical diagnosis only -> prenatal imaging

    • Clinical and genetic diagnosis -> genetic testing and prenatal imaging

  • No family history: population risk (very low)

    • Routine prenatal care

  • Population risk of birth defects 2-3%


Testing strategies

Testing Strategies

  • Available

    • Prenatal imaging

    • Fetal DNA testing (amniotic fluid or CVS)

  • Not Available

    • Maternal serum screening

    • Biochemical testing (amniotic fluid)


Imaging diagnosis

Imaging diagnosis

  • Consistent finding

    • Cerebellar vermis hypoplasia

      • Molar tooth sign not seen before 24 weeks

  • Supportive findings (rare)

    • Polydactyly

    • Cystic kidneys

    • Encephalocele

    • Increased respiratory rate


Vermis hypoplasia us

Vermis hypoplasia US

Superior vermis

intact

Inferior vermis

absent


Vermis hypoplasia fetal mri

Vermis hypoplasia fetal MRI

21 wks

Affected

22 wks

Unaffected


Molar tooth sign in utero

Molar tooth sign in utero

29 wks gestation

Post-natal


Polydactyly in utero

Polydactyly in utero

2

3

1

4

5

6

Aslan et al. 2002


Encephalocele in utero

Encephalocele in utero

US (not JS)

Fetal MRI (JS)


Specific imaging strategy

Specific imaging strategy

  • Usual prenatal care and screening

  • Consultation with a tertiary care center

  • 16-18 week US

  • 20 week US

  • 20-22 week fetal MRI

adapted from Doherty et al. 2005

We are happy to consult with OB providers/radiologists about imaging

diagnosis. We prefer to be involved starting before/early in the pregnancy.


Imaging diagnosis1

Imaging diagnosis

  • Advantages:

    • Non-invasive

    • Can visualize brain, fingers, kidneys

    • Can be repeated throughout pregnancy

    • Relatively inexpensive

  • Disadvantages:

    • Technician-dependent

    • Radiologist-dependent

    • May not see subtle abnormalities

    • Late diagnosis


Background genetic testing

Background: Genetic Testing

Gene Estimated frequency

NPHP1 ~2%

AHI1 ~10%

CEP290 ~10%

RPGRIP1L ~5%

MKS3 ~10%

ARL13B <1%

CC2D2A ~10% INPP5E ?

TMEM216 ~ 4%

MKS1 ~ 2%

OFD1 <1%

TOTAL <50%

Frequency of mutations in patients with JS


Dna testing strategy

DNA testing strategy

  • Test affected child prior to next pregnancy


Dna testing strategy1

DNA testing strategy

  • Test affected child prior to next pregnancy

  • Test affected child prior to next pregnancy


Dna testing strategy2

DNA testing strategy

  • Test affected child prior to next pregnancy

  • Test affected child prior to next pregnancy

  • No mutation identified -> PND by imaging


Dna testing strategy3

DNA testing strategy

  • Test affected child prior to pregnancy

  • Test affected child prior to pregnancy

  • No mutation identified -> PND by imaging

  • Mutation identified

    • Preimplantation genetic diagnosis

    • Chorionic villous sampling

    • Amniocentesis


Dna collection techniques

DNA collection techniques

  • early placental tissue

  • 10-12wk gestation

  • Risks:

    • Miscarriage (1/100)

    • Infection

  • Less available in US

  • DNA dx 12-14 wks

Chorionic villus sampling


Dna collection techniques1

DNA collection techniques

Amniocentesis

  • fetal skin cells in fluid

  • >15 wk gestation

  • Risks:

    • Miscarriage (1/500)

    • Infection

    • Fluid leak

    • Fetal injury

  • DNA dx ~20+ wks


Making a decision

Making a Decision

  • Genetic Counselor or Geneticist can help

    • Discuss options

    • Provide resources and support

  • Consider contacting them before pregnancy or early in pregnancy

  • See www.nsgc.org for a list of local GC’s


Prenatal diagnosis pnd in joubert syndrome

Conclusions

  • Family history of JS

    • Known mutation -> PND by gene testing

    • No mutation -> PND by prenatal US & fetal MRI

  • No family history

    • JS not distinguishable from other cerebellar vermis hypoplasias before 24wks

    • Variable features can facilitate diagnosis

      • Encephalocele, polydactyly, cystic kidneys

  • After 27wks, dx possible by imaging alone


Acknowledgements

Acknowledgements

University of Washington Joubert Center

http://depts.washington.edu/joubert/

206-616-3788

[email protected]


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