prenatal diagnosis (pnd) in joubert syndrome

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– (Preimplantation genetic diagnosis)

• Allow for prenatal treatment

JS is autosomal recessive*

Recurrence risk = 25%

Reproductive options• Accept the risk without PND

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 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 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 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 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• 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

• Available–Prenatal imaging–Fetal DNA testing (amniotic fluid or CVS)

• Not Available–Maternal serum screening–Biochemical testing (amniotic fluid)

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

Superior vermisintact

Inferior vermisabsent

Vermis hypoplasia fetal MRI

21 wksAffected

22 wksUnaffected

Molar tooth sign in utero

29 wks gestation Post-natal

Polydactyly in utero

123

4

5

6

Aslan et al. 2002

Encephalocele in utero

Fetal MRI (JS)US (not JS)

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 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 TestingGene Estimated frequencyNPHP1 ~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• Test affected child prior to next pregnancy

DNA testing strategy• Test affected child prior to next pregnancy• Test affected child prior to next pregnancy

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 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

• 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 techniquesAmniocentesis• fetal skin cells in fluid• >15 wk gestation• Risks:

– Miscarriage (1/500)– Infection– Fluid leak– Fetal injury

• DNA dx ~20+ wks

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

• 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

Conclusions

Acknowledgements

University of Washington Joubert Center http://depts.washington.edu/joubert/

206-616-3788joubert@uw.edu