medizinische fakultät carl gustav carus institut für ...€¦ · gajal-rezius cells - reelin pial...
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Medizinische Fakultät Carl Gustav Carus Institut für Klinische Genetik Professur Evelin Schröck
Lissencephaly
Nataliya Di Donato, MD
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Lissencephaly overview
1. Clinical forms
2. Mutational landscape
3. Genotype-phenotype correlation
4. Genetic counseling
5. Clinical management
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How many images with lissencephaly?
PMG COB LIS
LIS LISN
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Lissencephaly (LIS) - definition
Images from http://www.vaporfi.com, http://www.celestialhealing.net, http://www.clker.com
“lissos” – smooth “enkephalos” – in the head
“”walnut” versus “hazelnut”
“human “mouse
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LIS – spectrum of malformations with insufficientneuronal migration
Normal Agyria (AGY) Pachygyria (PGY)
AGY-PGY defined as abnormally thick cortex with reduced orabsent cerebral convolutions and smooth brain surface and gray-white borderSBH – abnormal bands of gray matter beneath a normallyappearing cortex (although sulci may be very shallow)
BandHeterotopia
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LIS – rediced gyration with smooth surface andgray-white border.
PMG COB LIS
LIS LIS
COB
LISLIS
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21 LIS types based on MRI imaging
Lissencephaly types based on imaging Häufigkeit Vererbung
LIS with cerebellar hypoplasia, Agyria diffuse (thick or thin cortex) 4% AD/AR
Classic thick lissencephalyAgyria diffuse 6% AD/Xchr
Agyria-pachygyria p>a (mixed) 30% AD
Agyria-pachygyria a>p (mixed) << 1% Xchr
Pachygyria p>a (complete or partial) 13% AD
Pachygyria a>p (complete or partial) 5% Xchr/AD
Pachygyria p>a with non-cortical malformations1 5% AD
Pachygyria a>p with non-cortical malformations << 1% AD
Pachygyria-band a>p (complete or partial) 1% AD/XchrTubulinopathy-related dysgyriaDysgyria p>a (complete or partial) 11% AD
Dysgyria a>p (complete or partial) - ADSubcortical band heterotopiaSBH diffuse thick (band >5 mm) 10% Xchr
SBH diffuse thin (band <5 mm) 3% Xchr
SBH partial p>a (band thick or thin) 3% AD
SBH partial a>p (band thick or thin) 1% XchrThin undulating lissencephalyPachygyria a>p thin with cerebellar hypoplasia2 1% AR
Pachygyria a>p thin with normal cerebellum 4% AR
Pachygyria t>p>a thin with ACC, abnormal WM 1% Xchr
Microlissencephaly (MLIS)
MLIS with cerebellar hypoplasia (TUB features) 2% AD / AR
MLIS with MOPD1 <<1% AR
MLIS Barth type <<1% AR?
Di Donato et al. AJMG 2017
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Major groups based on cortical morphology
LIS major subtypes Frequency Inheritance
Diffuse agyria with cerebellar hypoplasia 4% AD/AR
Classic pachygyria (cortex > 10 mm) 60% AD
Tubulinopathy-related dysgyria 11% AD
Subcortical band heterotopia 17% Xchr/AD
Pachygyria with cortex 5-10 mm 6% AR
Microlissencephaly (MLIS) 2% AD/AR
Di Donato et al. AJMG 2017
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Normal cortex è 3-4 mm• FL motor strip è 4.5 mm• OL visual cortex è 2.5 mm
“Classic” LIS è 10-20 mm
“Thin” LIS è 5-10 mm
New criterion: cortical thickness
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LIS groups with different cortical thickness
normal Pachygyria withcortex > 10 mm
Pachygyria withcortex < 10 mm
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Example LIS with cortex 10-20 mm
o Agyria, mixed agyria-pachygyria, pachygyria-band
o Anterior and posterior gradient
o Isolated or with additional non-cortical malformations
Normal Anteriorgradient
Posteriorgradient
Diffuseagyria
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Lissencephaly – always genetic20 genes and diagnostic yield over 80%
Di Donato et al. 2018 Genet. Medicine.
CRADDCDK5NDE1
KIF2AKIF5CRNU4ATAC
2018-2019 – 3 novel LIS genes:APC2, MACF1, MAST1
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15 of 20 LIS-associated genes are encoding forstructural or regulatory cytoskeletal proteins
Di Donato et al. 2018 Genet. Medicine.
Actomyosin
Centrosome
Microtubules
F-actin
Moon&Wynshaw-Boris, 2013
Protein networks Genes
Reelin signaling RELN, VLDLR
Actin / associated proteins ACTB, ACTG1, DCX
Tubulins TUBA1A, TUBB, TUBB2B,TUBB3, TUBA8
Microtubule motor proteins DYNC1H1, KIF5C, KIF2A
Complex microtubuliassociated proteins (MAPs)
CDK5
Centrosomal MAPs LIS1 (aka PAFAH1B1), TUBG1,NDE1
Forebrain transcription ARX
Apoptosis CRADD
Gajal-Rezius cells - Reelin
Pial membrane
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LIS standard diagnostic strategy
Di Donato et al. 2018 Genet. Medicine.
Phenotype analysis 1• LIS or LIS syndrome?• Non-LIS MCD?Ø Expand target
Lab-3 Genome-wide• WES vs. WGS• FISH telomere probes
orDeep coverage for MOS• Targeted SEQ panel
≥800x detect 1% AAF
Lab 1 CMA for CNVs• Genome-wide• Exon level prefered• SNP array preferred
Phenotype analysis 2• Does positive test fit?• Does negative test
exclude or not?• Will more testing find
the cause?
Lab-2 Targeted SEQ• Prefer exome slice
with coverage ≥ 50x• Alternative individual
genes with coverage≥100x
• Must have exon levelcoverage for CNV
Phenotype analysis 3• Does positive test fit?• Does negative test
exclude or not?• Counseling for best
diagnosis• Consider referral to
research center
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LIS expert diagnostic strategy
Initial phenotype analysisCNV analysisTargeted sequencing /exome sliceWhole exome sequencing
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Tubulinopathy-associated dysgyria
PolymicrogyriaDysgyriaPachygyria
Guerrini & Dobyns. Lancet Neurol. 2014 Jul;13(7):710-26
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Tubulinopathies – other features
Agenesis ofcorpus callosum
Largetectum
Cerebellarhypoplasia-dysplasia
NL
Oegema et al. 2015doi: 10.1093/hmg/ddv250
NL
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Tubulinopathies – other features
Agenesis ofcorpus callosum
Largetectum
Cerebellarhypoplasia-dysplasia
NL
Oegema et al. 2015doi: 10.1093/hmg/ddv250
NL
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Tubulinopathies – other features
Agenesis ofcorpus callosum
Largetectum
Cerebellarhypoplasia-dysplasia
NL
Oegema et al. 2015doi: 10.1093/hmg/ddv250
NL
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Tubulinopathy is a recognizable phenotype withoutstrict correlation with the responsible gene; expectmissense mutation in TUB genes
Di Donato et al. 2018 Genet. Medicine.
Actomyosin
Centrosome
Microtubules
F-actin
Moon&Wynshaw-Boris, 2013
Protein networks Genes
Reelin signaling RELN, VLDLR
Actin / associated proteins ACTB, ACTG1, DCX
Tubulins TUBA1A (5%), TUBB,TUBB2B, TUBB3, TUBA8
Microtubule motor proteins DYNC1H1 (3%), KIF5C,KIF2A
Complex microtubuliassociated proteins (MAPs)
CDK5
Centrosomal MAPs LIS1 (aka PAFAH1B1), TUBG1,NDE1
Forebrain transcription ARX
Apoptosis CRADD
Gajal-Rezius cells - Reelin
Pial membrane
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LIS expert diagnostic strategy
Initial phenotype analysisCNV analysisTargeted sequencing /exome sliceWhole exome sequencing
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Single gene test for strong clinical diagnosis
Diffuse SBHDCX
Diagnostic yield> 95%
XLAGARX
Diagnostic yield ~ 100%
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Novel LIS gene with a distinct phenotype
Lee et al. Biallelic loss of human APC2, encoding adenomatous polyposis coli protein 2, leads to lissencephaly,subcortical heterotopia, and global developmental dela. AJHG. 2019. In press
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• Baraitser-Winter-Cerebrofrontofacial syndrome(ACTB, ACTG1)
PMID: 21552264, PMID: 3802558, PMID: 22578326
Single gene tests for recognisable syndromes
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Single gene test for the most frequent gene
LIS1 (aka PAFAH1B1) – mutations in 40% of LIS patients
Diffuse AGY Posterior AGY Posterior PGY Posterior SBH
del17p13.3DCX
del17p13.3intragenic LIS1 del
LoF mutationsTUBA1A: p.R402C
LIS1DYNC1H1TUBG1…
mosaic LIS1…
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Genetic counseling by unknown cause
LIS major subtypes Frequency Inheritance
Diffuse agyria with cerebellar hypoplasia 4% AD/AR
Classic pachygyria (cortex > 10 mm) 60% AD
Tubulinopathy-related dysgyria 11% AD
Subcortical band heterotopia 17% Xchr/AD
Pachygyria with cortex < 10 mm 6% AR
Microlissencephaly (MLIS) 2% AD/AR
Di Donato et al. AJMG 2017
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Patient prognosis and management changesdepending on the causative mutation
Herbst et al. Brain & Development 38 (2016) 399-406.
LIS1 - all 22 patients had early onset drug-resistantepilepsy
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Distinct response to antiepileptic drugs
Lamotrigine
Valproate
Levetiracetam
Sulthiame
Topiramate
Oxcarbazepine
Herbst et al. Brain & Development 38 (2016) 399-406.
Vigabatrin
Phenobarnital
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Can an early developmental disorder be treated?
Yamada et al. NatMed.2009. October;15(10):1202–1207. Toba et al. Sci Rep. 2013; 3: 1224.
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LIS1 is essential for the regulation of cytoplasmicdynein und facilitates intracellular transport duringthe whole life
Yamada et al. EMBO J. 2008 Oct 8; 27(19): 2471–2483. Guerrini & Dobyns. Lancet Neurol. 2014 Jul;13(7):710-26
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Summary
1. LIS - genetic disorder with the diagnostic yield > 80%
2. LIS1 (4 0%) and DC X(23 %) are the most frequently
mutated genes
3. Standard and expert diagnostic strategies
4. Genotype-phenotype correlation allows prediction of
the causative genes or inheritance pattern
5. Therapy possible - > LIS-associated genes function
through the whole life
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Acknowledgement
Institut für Klinische GenetikTU Dresden, Dresden, Germany
Dobyns Lab, CIBR, SeattleChildren’s Research Institute,
Seattle, WA
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