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 - PowerPoint PPT PresentationTRANSCRIPT
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Prenatal diagnosis (PND) in
Joubert syndrome
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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
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JS is autosomal recessive*
Recurrence risk = 25%
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Reproductive options• Accept the risk without PND
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Reproductive options• Accept the risk without PND• Accept the risk and consider PND:
– To prepare for an affected child– To terminate an affected pregnancy
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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
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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
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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
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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.
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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%
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Testing Strategies
• Available–Prenatal imaging–Fetal DNA testing (amniotic fluid or CVS)
• Not Available–Maternal serum screening–Biochemical testing (amniotic fluid)
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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
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Vermis hypoplasia US
Superior vermisintact
Inferior vermisabsent
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Vermis hypoplasia fetal MRI
21 wksAffected
22 wksUnaffected
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Molar tooth sign in utero
29 wks gestation Post-natal
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Polydactyly in utero
123
4
5
6
Aslan et al. 2002
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Encephalocele in utero
Fetal MRI (JS)US (not JS)
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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.
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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
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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
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DNA testing strategy• Test affected child prior to next pregnancy
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DNA testing strategy• Test affected child prior to next pregnancy• Test affected child prior to next pregnancy
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DNA testing strategy• Test affected child prior to next pregnancy• Test affected child prior to next pregnancy• No mutation identified -> PND by imaging
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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
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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
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DNA collection techniquesAmniocentesis• fetal skin cells in fluid• >15 wk gestation• Risks:
– Miscarriage (1/500)– Infection– Fluid leak– Fetal injury
• DNA dx ~20+ wks
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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
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• 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
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Acknowledgements
University of Washington Joubert Center http://depts.washington.edu/joubert/