diagnostic approach to malformations of cortical development
TRANSCRIPT
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Diagnostic approach to
malformations of cortical
development
Renske Oegema, MD, PhD
clinical geneticist UMC Utrecht WKZ, the Netherlands
EPNS satellite 2019
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Overview
• Introduction to MCD
• Diagnostic approach
• Specific recommendations and syndromes
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Malformations of Cortical Development
• = MCD
• Most individually rare
• As a group burden on healthcare and society
polymicrogyria
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Malformations of Cortical Development
• = MCD
• Most individually rare
• As a group burden on healthcare and society
heterotopia
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1. Abnormal neuro-glial proliferation or
apoptosis
a. Microcephalies
b. Megalencephalies
2. Abnormal neuronal migration
a. Lissencephalies / Band heterotopia
b. Cobblestone complex
c. Nodular heterotopia
3. Abnormal cortical organization
a. Polymicrogyria
4. Not otherwise specified
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Defect of neuronal proliferationmigrationproliferation
www.virology.ws
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Lui et al Cell 2011
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Diagnosis?
Periventricular
nodular
heterotopia
Female
Normal cognition
No seizures
Congenital heart
disease of outflow
tract
X-linked PVNH:
FLNA mutation
G. Mancini
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• 22m- old boy
• Motor delay
• Spastic
paraplegia
• Polymicrogyria
Diagnosis?
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• Del 1p36.3
• Dup 2p13p23
• Del 4q21q22
• Del 6q26q27
• Del 13q3
• Del 18p11
• Del 21q2
• Del 22q11.2
Non-genetic
• Vascular, twinning
• Infectious
• Microcephaly syndromes
• Micro syndrome (RAB3GAP1,
RAB3GAP2, RAB18)
• Megalencephaly syndromes
• RTTN
• DDX3X
• Chudley-McCullough (GPSM2)
• Goldberg-Shprintzen (KIAA1279)
• Fumaric aciduria
• Zellweger syndrome
• Aicardi syndrome
• Knobloch syndrome
• Vici syndrome
• Joubert syndrome
• ….
Polymicrogyria - etiologyChromosomal Monogenic
[Guerrini and Dobyns, Lancet Neurol 2014]
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polymicrogyria
Guerrini & Dobyns 2014
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To
• Inform the patient
• Target patient
management
• Predict outcome
• Counsel risk to family
members
• Offer reproductive
choices
Why diagnose?
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• MCD expertise
– Neuroradiologist
– (pediatric) Neurologist
– Clinical geneticist
– Molecular geneticist +
lab
– Opthalmologist
– Scientist
– Etc.
However:
• Not available in every
center
• Knowledge is
fragmented
• No standardized
approach
How to diagnose?
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European Network
COST Action 2017-2021
• To bring together clinicians and researchers in the
field of brain malformations,
• to create an interdisciplinary network advancing the
understanding of cortical malformations
pathophysiology,
• and to translate this knowledge to improve the
diagnostic and clinical management of the patients.
• www.neuro-mig.org
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Working groups 1-5
WG1: Integration, harmonisation and standardisation of
clinical phenotyping and medical management
WG3: Molecular genetics and functional genomics
Paper:
Malformations of cortical development, international
consensus recommendations on diagnostic workup
Renske Oegema, Nataliya Di Donato et al. (submitted)
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Neuro-MIG meeting Lisbon sept 2018
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Methods
• Literature review, expert input
– Diagnostic yield
– MCD gene lists
• Group discussions
• Feedback from all COST members
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Microarrays:
LIS: 9% (del 17p13.3)
PNH: 36%
PMG: 6-9%
MIC: 7%
Targeted gene testing:
SBH: 79% (LIS1/ DCX)
PNH: 9-100% (FLNA)
MIC: 10-40% (ASPM)
Regensburg MCD cohort:
Yield w/o MRI: 18%
Yield w/ MRI: 37%
Average 1.5 gene tested
Diagnostic yield
0
10
20
30
40
50
60
70
80
PNH LIS COB PMG MIC
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22q11.2 microdeletion
Hemiparesis, mild cognitive delay
Unilateral polymicrogyria
Grazia Mancini
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NGS
• No large gene panel studies published
• Yield 15-20% in diagnostic labs
– Clinical info often lacking, not all MCD?
Array + WES
1 study 54 MCD patients [Wiszniewski 2018]:
definitive (9/16) or presumptive (7/16) molecular
diagnosis in 16/54 (30%)
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Optimal diagnostic strategy
• Broad approach• 1 gene > several phenotypes, eg TUBA1A, WDR62
• Low quality imaging
• Molecular diagnosis should not rely on resources/ physician’s
expertise
• MCD gene list
• Diagnostic work flow
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• List of > 200 MCD genes
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• Diagnostic yield
– Literature review, personal communication
• Optimal diagnostic strategy
• Special recommendations and syndromes associated
with brain malformations
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• Macrocephaly
• Capillary
malformations
• MRI:
• Megalencephaly
• PMG
MCAP syndrome (PIK3CA 32% Pro104Leu)
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Mosaicism
• +- Macrocephaly
• +- MPPH syndrome
• Mutations in 19/126 patiënten with PMG (15%)
– De novo germline and mosaic mutations
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• Examine carefully
• Extract DNA from
affected tissue
• Or saliva/ skin fibroblasts
• Targeted deep
sequencing (500-5000x)
• Validate variant eg with
ddPCR
• Consider especially in
MEG and FCD (and PMG)
Detecting mosaicism
Mirzaa 2016
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• 2y girl
• Focal seizures
• Hemiplegia
• OFC -2.5 SD
• Scar macula
• CMV +
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• 22m-old boy
• Motor delay
• Spastic
paraplegia
• CMV +
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Prenatal anomalies:
IUGR, microcephaly
ventriculomegaly
lung agenesis?
clenched fists
Postpartum
seizures
PMG
oxygen dependant
arthrogryposis
thrombocytopenia
CMV +
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Mancini
Fry
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• Hirschsprung’s disease
• DD/ ID
• Ptosis
• Dysmorphic features
• Bi-allelic mutations in KIAA1279 (KBP).
Goldberg-Shprintzen syndrome
Brooks. AJHG 2005
Murphy 2006
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Take home messages MCD
• Broad spectrum of presentation and etiology
• Associated with both common and rare syndromes
• Think chromosomal, monogenic and non-genetic
• Pattern recognition vs general workflow > diagnosis
• Collaborate, share, publish!
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Thank you!
UMC Utrecht - WKZ