Truncation and microdeletion of EVC accompanied by novel ... · Truncation and microdeletion of EVC...
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Truncation and microdeletion of
EVC accompanied by novel EFCAB7
missense mutation in Ellis-van
Creveld syndrome with atypical
congenital heart defect
PEDIATRIC 2016 Atlanta, Georgia, U.S
Mar 30 2016
NGUYEN Tran Quynh Nhu, MD.
Department of Developmental Medical Sciences
School of International Health, Graduate School of Medicine
The University of Tokyo
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BACKGROUND
• Academic education:
2015-2018: Ph.D
School of Medicine, The University of Tokyo, JAPAN
2013-2015: M.Sc
School of Medicine, The University of Tokyo, JAPAN
2009-2011: DIU (pediatric emergency and neonatology)
Universities of France + Pham Ngoc Thach Medical University, VIETNAM
2001-2007: Medical doctor
Ho Chi Minh City University of Medicine & Pharmacy, VIETNAM
• Licenses & certificates:
2011: DIU (Diplôme inter-universitaire d’urgence pédiatrique)
2010: Medical license
2010: PALS (Certificate of Pediatric Advanced Life Supports)
2009: Certificate of echocardiography and cardiac pathology
• Work:
2008-2013: Cardiologist
Children’s Hospital 2, VIETNAM
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27.5% 25.1% 25.7% 0
2000
4000
6000
8000
10000
12000
2013 2014 2015
Congenital defects
Congenital heartdefects
Congenital defects 2013-2015
in Children’s Hospital 2, Vietnam
Details of Congenital Heart defects
The number of congenital defects per year
21%
14%
18%
3% 5%
39% 22%
12%
15%
4% 7%
41%
20%
10%
17%
3% 7%
43%
VSD
ASD
PDA
AVSD
TOF
Others
2013 2014 2015 Children’s Hospital 2, Ministry of Health, Vietnam
2013-2015
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Ellis-van Creveld syndrome
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• Rare autosomal recessive ciliopathy
• Abnormalities: ectodermal, skeleton, heart (60%)
• 30% consanguineous couples
• Prevalence:
1/60000, 300 cases (worldwide)
5/1000 (Old Order Amish)
• Causative genes: EVC & EVC2
60-70% Mutation-positive cases
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• EVC/EVC2 protein:
located at basal
bodies (EvC zone)
of primary cilia
• Function: regulate
Hedgehog signaling
in skeletal, cardiac
development
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Caparros-Martin et al.,Human Molecular Genetics(2013)22:124-139
Mutations in EVC/EVC2 disrupt cilia-mediated
Hedgehog signaling
PTCH1
Smoothened
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EFCAB7&IQCE regulate Hh signaling by
tethering the EVC-EVC2 complex
SP TM Coiled coil EVC
SP βsan TM Coiled coil WEYER EVC2
ECH1 ECH2 EF EF EF EF EF EF EF EF EFCAB7
HP Coiled coil
conserved
Coiled coil
divergent IQ IQ AcidE IQ IQCE
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OBJECTIVES
• To identify genetic background for
Vietnamese EvC patients
• To identify molecules associated
with pathogenesis of EvC syndrome
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• Place : Dept. Cardiology, Children’s Hospital 2
Ho Chi Minh City, Vietnam
• Duration : 09/2013 up to present
• Materials : whole blood, buccal mucosa & medical data
MATERIALS
DIAGNOSIS at 16th ~20th weeks of gestation by fetal echography:
morphology, echocardiology
After birth: collect medical data, samples
FOLLOW-UP
Congenital heart defects
Every month
AVSD-CA: operation at 6~12 months
After operation: every 3~6 months
Oral and skeletal defects
Every 3~6 months
Intervention: ~3 year-old
After intervention: every year
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Clinical features of patients Features E1 E2 E3 E4 E5 E6 E7 E8
Polydactyly +++ ++ ++ +++ ++ +(R) - -
Syndactyly - - - - + - + ++
Congenital heart
defects cAVSD
pAVSD,
PS
cAVSD,
PS CA cAVSD CA ASD pAVSD
Narrow chest + + + ++ + - + -
Short stature 25th <2nd <2nd <2nd <2nd <2nd + 25th
Distal limb
shortening + + + + + - - -
Dysplastic nails +++ +++ +++ +++ +++ - + -
Tooth shape
abnormalities - - - - - + + -
Excess frenule - + - ++ - - - +
Hypodontia - - +/- - - - - -
Neonatal teeth - + - + - - - -
Others - - - - + + - -
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cAVSD complete artio-ventricular septal defect CA common atrium PS pulmonary
pAVSD partial atrio-ventricular septal defect ASD atrial septal defect stenosis
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Case E2: two novel compound heterozygous EVC2 mutations
Heterozygote
14 Father 6
14 Mother 6
c.2476C>T
14 E2 6
c.769G>T
c.769G>T
c.2476C>T
E2 Mother Father
E2 Mother Father
Short stature
Weyer acrofacial dysostosis
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Case E3: novel mutations in EVC and mRNA expression
c.1717C>G/EVC
4p16.2
centromere telomere EVC
16.4 kb microdeletion/EVC
E3 Mother Father
No mutation
CGH array result
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4p16.2
centromere telomere EVC
Control
E3/
Mother
4:5755743 - 4:5755841; 4:5755639 - 4:5755840, intron 10
4:5768927- 4:5769006; 4:5669007~, intron11
Inserted fragment, unknown origin
8 9 10 11 12
4:5752479 4:5768927
8 12 CAGA
~ 4:5752479, intron8
8 kb
7.5-
F M E3 C
2.5-
5-
kb
10-
16.4 kb microdeletion of EVC
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EFCAB7 point mutation
c.1171T>C/EFCAB7
Pusapati et al., Developmental cell (2014)28:483-496
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Case E3: SHORT CHORDAE
Hypothesis: EFCAB71171C may cause short chordae in EvC
by tethering with EVC, EVC2, IQCE at the base body of cilium.
Patient E3
Father E3
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DISCUSSION
• Different heterozygous mutations resulted in various
severity of phenotype
Phenotype-genotype relationship remains elucidated.
• Novel EFCAB7 variant was found in patients with atypical
cardiac defect; short chordae.
• Short chordae has never been reported in EvC
• EFCAB7 knockout mice showed AVSD
EFCAB7 might have roles in heart development and
formation.
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CONCLUSION
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Leu Val His
Arg
Tyr
(c)
C T T G T A T A T A G A
C
Leu Val His
Arg
Tyr
(c)
C T T G T A T A T A G A
C
Leu Val His
Arg
Tyr
(c)
C T T G T A T A T A G A
C
• The novel compound heterozygous mutations in
EVC2 (c.769G>T, c.2476C>T) were disease-
causative.
• A novel point mutation (c.1717C>G) and 16.4 kb
heterozygous deletion of EVC caused EvC
phenotype.
• EFCAB7 variant (c.1171T>C) was detected for the
first time in EvC.
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ACKNOWLEDGEMENTS
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