x-gebonden verstandelijke beperking - nvavgnvavg.nl/wp-content/uploads/2016/03/van-esch-x... ·...
Post on 18-Feb-2018
231 Views
Preview:
TRANSCRIPT
X-gebonden verstandelijke
beperking
Hilde Van Esch
X-gebonden verstandelijke
beperking
…een beetje geschiedenis
Verstandelijke beperkingPrevalentie
+/- 2 tot 3% in Westerse populatie
85% mild ID
10% matig ID
3 to 4% ernstig ID
1 to 2% diep ID (DSM-IV criteria)
>> 20 tot 30%
Verstandelijke beperkingXLID
“ unusually large number of genes on the X
chromosome code for proteins important for
brain function”
“10% of human genetic defects that cause
Intellectual Disability reside on the X
chromosome, even though it carries less
than 4% of known human genes”
“the X chromosome is easy to handle by
geneticists”
XLID
The European X-linked mental
retardation (XLMR) consortium
iGOLD consortium
RPSKA3 (RSK2) (19)
13
25
28
1112
26
27
24
23
22.3
22.2
22.1
21.3
21.2
21.1
11.4
11.3
11.1
21.1
21.2
21.3
22.122.222.3
11.23
11.2211.21
AFF2 (FMR2, FRAXE)
GDI1 (41, 48)
OPHN1 (60)
PAK3 (30,47)
CDKL5 (STK9)
IL1RAPL1 (21,34)
TM4SF2 (58)
ACSL4 (FACL4) (63,68)
ARHGEF6 (PIX) (46)
MECP2 (16,64,79)SLC6A8
AGTR2 (88)
FGDY
NLGN4
PQBP1 (55)ZNF81 (45)
ZNF674 (92)
FTSJ1 (9,44)
KDM5C (SMX, JARID1C)
DLG3 (8, 90)
SLC16A2 (MCT8)
UPF3B (62)
ZDHHC15 (91)NLGN3
KLF8 (ZNF741)
ZNF41 (89)
AP1S2 (59)
HUWE1 (17, 31)**
SRPX2
NDUFA1
RAB39B (72)
MAGT1 (IAP)
IQSEC2 (1,18)
ATRX (XNP)
CLCN4 (49)
THOC2 (12)
HCFC1 (3)
XLID-hypogonadism-tremor (CUL4B)
Coffin-Lowry (RPSKA3, RSK2)
Aarskog (FGDY)
Telecanthus-hypospadias (MID1)
Pyruvate dehydrogenase deficiency (PDHA1)Glycerol kinase deficiency (GKD)
Duchenne muscular dystrophy (DMD)
Ornithine transcarbamoylase deficiency (OTC)Monoamine oxidase-A deficiency (MAOA)Norrie (NDP)
Pelizaeus-Merzbacher (PLP)Mohr-Tranebjaerg (TIMM8A, DDP)
Lissencephaly, X-linked (DCX)
Lowe (OCRL1)
Simpson-Golabi-Behmel (GPC3) Lesch-Nyhan (HPRT)
Fragile XA (FMR1)Mucopolysaccharidosis IIA (IDS)
Myotubular myopathy (MTM1)Adrenoleukodystrophy (ABCD1)
Hydrocephaly-MASA spectrum (L1CAM)
Rett, PPM-X (MECP2)* Incontinentia pigmenti (IKBKG, NEMO)Dyskeratosis congenita (DKC1)
-Thalassemia Intellectual Disability
XLID-hypotonic facies, Carpenter-Waziri,
Holmes-Gang, Chudley-Lowry, XLID-arch
fingerprints-hypotonia, Smith-Fineman-Myers(?)
(ATRX, XNP,
XH2)
XLID-optic atrophy (AGTR2)
Partington, West, Proud, XLAG (ARX)
Börjeson-Forssman-Lehmann (PHF6)
Oral-facial-digital I (OFD1)
Spermine synthase deficiency (SMS)
XLID-growth hormone deficiency (SOX3)
Periventricular nodular heterotopia, Otopalatodigital I, Otopalatodigital II, Melnick-Needles
(FLNA, FLN1)
Phosphoglycerate kinase deficiency (PGK1)Menkes disease (ATP7A)
XLID-infantile seizures, Rett like (CDKL5, STK9)
Nance-Horan (NHS)
XLID-cerebellar dysgenesis (OPHN-1)
XIDE (Renin receptor; ATP6AP2)
Autism (NLGN4)
OFCD, Lenz microphthalmia (BCOR)
XLID-choreoathetosis (HADH2)
Stocco dos Santos (SHROOM4, KIAA1202)XLID-cleft lip/palate (PHF8)
Epilepsy/macrocephaly (SYN1)
Allan-Herndon (SLC16A2, MCT8)
Creatine transporter deficiency (SLC6A8)
Danon cardiomyopathy (LAMP2)
Arts, PRPP synthetase superactivity (PRPS1)
Cornelia de Lange, X-linked (SMC1L1, SMC1A)
Opitz-Kaveggia FG, Lujan (MED12, HOPA)
MIDAS (HCCS)Turner, XLID-hydrocephaly-basal ganglia calcification
XLID-nail dystrophy-seizures (UBE2A)
*XLID-hypotonia-recurrent infections (MECP2 dup)
XLID-macrocephaly-large ears (BRWD3)
XLID-macrocephaly-Marfanoid habitus (ZDHHC9)
Christianson, Angelman-like (SLC9A6)
FG/Lujan phenotype (UPF3B)
Graham coloboma (IGBP1)
Autism (RPL10)
XLID-short stature-muscle wasting (NXF5)
Cantagrel spastic paraplegia (KIAA2022)
VACTERL-hydrocephalus (FANCB)
Mitochondrial encephalopathy (NDUFA1)
Chiyonobu XLID (GRIA3)
Renpenning, Sutherland-Haan,
Cerebropalatocardiac (Hamel),
Golabi-Ito-Hall, Porteous
(PQBP1)
13
25
28
1112
26
27
24
23
22.3
22.2
22.1
21.3
21.2
21.1
11.4
11.3
11.1
21.1
21.2
21.3
22.122.222.3
11.23
11.2211.21
XLID-hyperekplexia-seizures (ARHGEF9)
Goltz (PORCN)
(AP1S2)
Epilepsy-intellectual disability limited to females (PCDH19)
Ichthyosis follicularis, atrichia, photophobia (MBTPS2)
Microcephaly-pachygyria-dysmorphism (NSDHL)
XLID-macrocephaly-seizures-autism (RAB39B)
XLID-macrocephalyJuberg-Marsidi-Brooks
(HUWE1)
Chaissaing-Lacombe chondrodysplasia (HDAC6)
Martin-Probst (RAB40AL)
XLID-nystagmus-seizures (CASK)
MEHMO (EIF2S3)
N-Alpha acetyltransferase deficiency (NAA10)
TARP (RBM10)
Wilson-Turner (LAS1L)
Cornelia de Lange, X-linked (HDAC8)
XLID-Rolandic seizures (SRPX2)
Syndromal
XLID genes
Greenwood Genetic Center, updated March 2012
Piton et al 2013 AJHG
maar …
Verstandelijke beperking
Belang van diagnose?
Turner G. et al., Clin. Genet. 2008
X-gebonden verstandelijke
beperking
Waarom enkel naar X kijken als het ganse
genoom/exoom ter beschikking is?
Auteur Approach Aantal
patiënten
Inclusie
criteria
X-gebonden
bewezenMoeder
draagster?
De Ligt J et al,
NEJM
WES 100 IQ<50 3% 3/3
overgeërfd
Rauch A et al,
Lancet
WES 51 Non-
syndromaal ID
10%
(jongens)
1/3
Redin C et al,
J Med Genet
Targeted
panel 217
106 ID 15% 12/16
Verstandelijke beperkingBelang van X ?
ORIGINAL ARTICLE
X-exome sequencing of 405 unresolved families
identifies seven novel intellectual disability genesH. Hu1,41, J Chelly3,4, H Van Esch5, M Raynaud6,7,8, APM de Brouwer9, S Weinert10,11, G Froyen12,13, SGM
Frints14,15, F Laumonnier6,7, T Zemojtel2, MI Love2, H Richard2, A-K Emde2, M Bienek1, C Jensen1, M Hambrock1, U
Fischer1, C Langnick10,
W Wissink-Lindhout9, N Lebrun3,4, L Castelnau3,4, J Rucci3,4, R Montjean3,4, O Dorseuil3,4, P Billuart3,4, T
Stuhlmann10,11, M Shaw16,17, MA Corbett16,17, A Gardner16,17, S Willis-Owen16,18, C Tan16, KL Friend19, S
Belet12,13, KEP van Roozendaal14,15,
M-P Moizard6,7,8, N Ronce6,7,8, R Sun2, S O’Keeffe2, R Chenna2, A van Bömmel2, J Göke2, A Hackett20, M Field20, L
Christie20, J Boyle20, E Haan16,19, J Nelson21, G Turner20, G Baynam21,22,23,24, G Gillessen-Kaesbach25, U
Müller26,27, D Steinberger26,27, B Budny28, M Badura-Stronka29, A Latos-Bieleńska29, LB Ousager30, P Wieacker31, G
Rodríguez Criado32, M-L Bondeson33, G Annerén33, A Dufke34, M Cohen35, L Van Maldergem36, C Vincent-Delorme37,
B Echenne38, B Simon-Bouy39, T Kleefstra9, M Willemsen9, J-P Fryns5, K Devriendt5, R Ullmann1,42, M Vingron2, K
Wrogemann1,40, TF Wienker1, A Tzschach1, H van Bokhoven9, J Gecz16,17, TJ Jentsch10,11, W Chen1,10, H-H
Ropers1 and VM Kalscheuer1
Verstandelijke beperkingNieuwe genen op X ?
Enkele voorbeelden van nieuwe X-gebonden genen
UBE2A
UBE2A
UBE2A
Piton et al 2013 AJHG
UBE2A
Moderate to severe ID
No speech
Dry skin - hirsutism
Facial (adults): synophris, large head, broad neck, upslant eyes
Occasionally: epilepsy, difficult behavior
UBE2A encodes a member of the E2 ubiquitin-conjugating
enzyme family. This enzyme is required for post-replicative
DNA damage repair.
THOC2
Kumar et al 2015 AJHG
T134 MRX12 L 22 D45
III-3 IV-1 IV-2 IV-17 V-
11 IV-13 V-2 V-13 VI-12 VI-13 III-7 III-8 II-5 III-2 III-3 III-4 IV-4 IV-7 IV-8
Age (yrs) 60 50 76 62 50 14 9 30 28 44 43 42 34 24 30 38
Neurologic
features
Intellectual
disabilityMo Mo Mo Mo-Se Mi Mo Mo Mi Mo Mi Mo Mo Mi-Mo
Mo-
SeMo Mo Se Mi-Mo Mi
Speech
problems+ - + - + + + + + + - - + + + + + - -
Hypotonia + + + + - + - - + + - - - + - - + - -
Hyperkinesia - - - - - - - - - - + + + - - - - -
Tremor - - - + + - + + - - - - - - - - + + +
Epilepsy + - + - - - - - - - - - - + - - + + -
Gait
disturbances+ - - + - - + - - - - - - + - - + -** - **
Behavior
problems- - - - - - + - - - + + + + - + - + -
Anxiety
problems- - - + - - + - - - - - - - - - - - -
Brain MRI/CT
results CCC,
GL - na na na na N na na - VM na na
WV,
CH CVD
Parameters
Microcephaly - - + + + - - - + + - - - - - - - - -
Short stature
(≤P3)- - - + + + + + + + * - + + + + + - - -
Overweight
(BMI≥25)+ - - + + - - + - + + + + - + -
Dysmorphisms
Broad high
forehead- - - + - - - - - - + + - - - - na - -
High palate - - - + + + + - + + - - - - - - na na na
Large ears (>2
SD)- - - + - + + - - - - - - - - na - na
Small
penis/microorc
hidism
- - - na na na na na - - + + - + na + na na na
Truncal obesity - - - + + + + + - - + + + + + + na na na
THOC2
Variable degrees of ID
speech delay
elevated BMI
short stature
seizure disorders
gait disturbance and tremors
THOC2 encodes a subunit of the highly conserved TREX
mRNA-export complex, essential for export of mRNA from the
nucleus to the cytoplasma
DDX3X
Development
Intellectual disability or
developmental delay100% 38/38
Mild or mild-moderate
disability26% 10/38
Moderate or moderate-
severe disability26% 10/38
Severe disability 40% 15/38
Developmental delay 8% 3/38
Growth
Low weight 32% 12/38
Microcephaly 32% 12/38
Neurology
Hypotonia 76% 29/38
Epilepsy 16% 6/38
Movement disorder
(including spasticity)45% 17/38
Behavior problems 53% 20/38
Brain MRI
Corpus callosum
hypoplasia35% 13/37
Cortical malformation 11% 4/37
Ventricular enlargement 35% 13/37
Other
Skin abnormalities 37% 14/38
Hyperlaxity 37% 14/38
Visual problems 34% 13/38
Hearing loss 8% 3/38
Cleft lip or palate 8% 3/38
Precocious puberty 13% 5/38
Scoliosis 11% 4/38
Females
Snijders-Blok et al 2015 AJHG
DDX3X
Variable degrees of ID
Other features including hypotonia, movement disorders, behavior problems,
corpus callosum hypoplasia and epilepsy.
Mutations in DDX3X are one of the more common causes of ID,
accounting for 1%-3% of unexplained ID in females.
No evidence of correlation of skewing of X inactivation with disease severity.
Mutations also found in XLID pedigrees
DDX3X encodes a conserved DEAD-box RNA helicase that is important in a
variety of cellular processes, including transcription, splicing,
RNA transport, and translation.
It is thought to be a key regulator of the WNT pathway
X-gebonden verstandelijke
beperking
Waarde van andere genetische testen?
Verstandelijke beperking
Studie X array in families met X gebonden
stamboom
X-Array-CGH detects aberration in about 10% of XLID families
- Higher hit rate in syndromic XLID
- 14 of 17 aberrations < 1 Mb
More duplications than deletions on the X chromosome Deletions on X might be lethal in males
Duplications on autosomes might have a milder phenotype
Duplication on X more easily detected compared to autosomes
Froyen G. et al, Hum Mut, 2008
Waarde van X array-CGH in jongens met sporadische ID ?
Study over 6 years (2004-2010)
2222 sporadic male patients with (non) syndromic ID
68 patients carried one or more X-CNVs (3.1%)
Classify ?
Clinical relevance ?
Waarde van X array-CGH in jongens met sporadische ID ?
all 3 criteria met< 3 criteria met 2 criteria met< 2 criteria met
no
nono
no
no
yes yes
yes
yesCNV association with ID already reported in
literature and /or databases (DECIPHER/ISCA)
Likely pathogenic CNV
CNV is a deletion CNV is a duplication
CNV reported in DGV or found in healthy individuals
CNV is recurrent deletion/duplication involving known ID gene(s)
Unclassified CNV
Criteria:•Brain expressed gene(s) present •De novo CNV or skewed X-inactivation in mother•Large gene-rich region
CNV contains known ID gene(s)
Criteria:•Brain expressed gene(s) present •De novo CNV or skewed X-inactivation in mother•Large gene-rich region
CNV contains known dosage-sensitive ID gene(s)
Pathogenic
CNV
Pathogenic CNV
Unclassified CNV
Unclassified CNV
Benign CNV
Likely pathogenic CNV
Pathogenic
CNV
yes
Proposed decision tree for classification of gene-containing
sporadic X-CNVs in males
Isrie M. et al, EJMG, 2012
Study over 6 years (2004-2010)
68 sporadic ID patients carried one or more X-CNVs (3.1%)
23 patients benign X-CNV
26 patients unclassified variants/risk factors
19 patients causal CNV (1% of total)
Waarde van X array-CGH in jongens met sporadische ID ?
Isrie M. et al, EJMG, 2012
Patient Aberration Size (Mb) Relevant genes for ID Origin/XI* Clinical characteristics
1 delXp22.31 6.0 SHOX, ARSE, ASMT, NLGN4X maternal/100:0
mild ID, ASD, short stature, mesomelic shortening of the
upper limbs, relative macrocephaly, cupped ears, simian
creases and mild cutaneous syndactyly
2 delXp22.32 4.3 NLGN4X, VCX3A, STS, VCX, KAL1 ndID, behavioral difficulties, ichthyosis, hypogonadotrophic
hypogonadism
3 delXp22.31 4.3 NLGN4X, VCX3A, STS, VCX, KAL1 nd developmental delay, hypospadias and ichthyosis
4 delXp22.31 4.3 NLGN4X, VCX3A, STS, VCX, KAL1 maternal/63:37 developmental delay
5 delXp22.31 1.9 VCX3A, STS, VCX nd severe ID, absent speech and behavioral problems
6 delXp22.31 1.6 STS, VCX nddevelopmental delay, ichthyosis, absent speech and
autistic features
7 delXp21.3 1.1 IL1RAPL1 nd moderate ID, behavioral problems
8
delXp11.21 0.0005 KLF8
maternal moderate ID, no speech, behavioral problems
delXq21.31 0.46 PCDH11X
9 delXq13.1 0.41 DLG3 nd moderate ID, epilepsy
10 delXq28 0.82 BCAP31, ABCD1, PLXNB3 ndsevere ID, bilateral deafness, spastic ataxia and
cryptorchidism
11 dupXp11.3 0.26 NDP maternal/77:23 DD, mild deafness and visual impairment
12 dupXp11.22 0.26 DGKK, SHROOM4 nd DD, choanal atresia, VSD and camptodactyly
13 dupXp11.22 3.8JARID1C, IQSEC2, HSD17B10,
HUWE1, PHF8, FGD1maternal/92:8
severe ID, growth retardation, minimal speech, rigid gait,
behavioral problems and dysmorphisms
14 dupXq12 0.79 AR, OPHN1, YIPF6 nd moderate ID and dysmorphic features
15dupXq13.3q
21.11.4 MAGEE1, FGF16, ATRX maternal/56:44 ID, agenesis of the corpus callosum, tall stature
16tripXq27.1q
2811.6 FMR1, AFF2 de novo severe ID, hypotonia, dysmorphic features
17 dupXq28 0.75SLC6A8, BCAP31, ABCD1, PLXNB3,
SRPK3, IDH3G, SSR4, PDZD4, L1CAMnd
moderate ID, speech delay, relative microcephaly,
dysmorphic features
18 dupXq28 0.44 BRCC3, RAB39B, CLIC2 maternal/85:15 mild ID, behavioral problems, psychosis
19 delXq23 4.4 HTR2C de novodevelopmental delay, behavioral problems, severe
speech delay, hoarse voice
Enkele voorbeelden van recurrente
X-gebonden copy number variations
MECP2 duplication syndrome
I:1 I:2
II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8II:9
III:1 III:2 III:3 III:4 III:5
II:10
III:6
II:11
III:7 III:8 III:9III:10
IV:1 IV:2
III:11
IV:3 IV:4 IV:5
LODscore: 1.23 at Xq28-Xqter
MECP2 duplication syndrome
Hypotonia + + + +
Epilepsy + + -- +
Profound MR + + + +
Spasticity LL>UL + + + +
Absence speech + + + +
Age at death -- 12 35 12
-0.90
-0.60
-0.30
0.00
0.30
0.60
0.90
0 20 40 60 80 100 120 140 160
position on X (Mb)
norm
aliz
ed
ratio
Van Esch H. et al, AJHG, 2005
Neurodevelopmental disorder
• MECP2 is an X-linked gene which encodes methyl-CpG-binding-protein 2 and plays
important role in gene regulation in the brain
• Heterozygous mutations are responsible for Rett syndrome in
females
• Duplication of the MECP2 gene with consequently higher
MECP2 protein dosage gives rise to severe ID in affected
males (Van Esch et al., AJHG, 2005), characterized by infantile
hypotonia, absence of speech, recurrent infections, seizures
and progressive spasticity predominantly of the lower limbs
MECP2 duplication syndrome
Overview clinical symptoms
Genomics ?
L36prox2
S49prox2
Q71F78
T33dist3T33dist3
Z49528bis
66N11
L36
S49
HT
K8210
X04-38
326037
T33
K9227
K8315
66N11 G6PD
FAM3A
AD
TREX-prox K8300
L1CAMquis
L1CAM8
FAM50A3
FAM50A5
K9228
CMS
FAM50A5 E316
15982G865E18
Q71F78 K9244
157E12
Z3 T88
PDZK4-3’
PNCK-3’
PLXNA3bis
T88prox3
SLC6A8
PLXNB3-5’
RPL10-5’-repeat
RPL10-5’-repeat
SLC6A8
8
8
8
7
2
5
5
6
2
3
1
4
DC1647
(41.5 kb)
DC1640
(26.5 kb)
DC1641
(9.7 kb)
DC1643
(38.3 kb)
DC1642
(37.7 kb)
DC1644
(11.3 kb)
DC1645
(11.3 kb)
DC1646
(35.5 kb)
Human genome segmental duplication database
IR2
(10 kb)
IR3
(10 kb)
Our analysis
152.4 152.5 152.6 152.7 152.8 152.9 153.0 153.1 153.2 153.3 153.4 153.5
Mb
1 2 43
IR1
(5 kb)
5 6 7 8
IR4
(9 kb)
IR5
(13 kb)IR6
(4 kb)
IR7
(7 kb)
IR8
(6 kb)
Recurrent Xp11.22 dup involving HUWE1 and HSD10B
Recurrent Xp11.22 dup involving HUWE1 and HSD10B
Froyen G. et al, AJHG, 2008
Recurrent Xp11.22 dup involving HUWE1 and HSD10B
Recurrent Xq25 dup involving STAG2
Kumar R. et al, HMG, 2015
Recurrent Xq25 dup involving STAG2
Typical clinical features Affected/accessible data (%)
Duplications and a triplication n = 33
ID
Borderline or not specified type 3/33 (9)
Mild/mild–moderate 16/33 (48)
Moderate 12/33 (36)
Severe 2/33 (6)
Autism spectrum disorder 4/15 (27)
Seizures 10/31 (32)
Behavior problems 19/28 (68)
Malar flatness 23/27 (85)
Thick vermillion 15/26 (58)
Facial hypotonia 16/27 (59)
Prognathism 16/26 (62)
Heavy eyebrows 7/17 (41)
Head circumference (OFC)
Normal 22/27 (81)
OFC < P10 1/27 (4)
OFC > P90 4/27 (15)
Height
Normal 19/28 (68)
Short stature 6/28 (21)
Tall stature 3/28 (11)
Recurrent Xq25 dup involving STAG2
STAG2 codes for a subunit of the cohesin complex that is essential for many cellular functions such as
sister chromatid cohesion and segregation (canonical roles) and maintenance of chromatin architecture,
DNA replication, DNA repair and transcriptional regulation
Take home message
In eXoom zit ook X
X gebonden stamboom: zeker array CGH en zo deze negatief X exoom
Ook bij sporadische ID mannen: array CGH
Vrouwen kunnen ook een X-gebonden verstandelijke beperking hebben
Clinical Genetics group (UZ)
Mala Isrie
Hilde Van Esch
Koen Devriendt
Thomy de Ravel
Joris Vermeesch
Jean-Pierre Fryns
Outside Leuven
B. Ceulemans, UIA, Belgium
S. Frints, Maastricht, The Netherlands
J. Chelly, Cochin, Paris, France
T. Bienvenu, Cochin, Paris, France
N. Bahi-Buisson, Necker, Paris, France
EuroMRX Consortium (http://www.euromrx.com/)
H-H Ropers, Berlin, Germany
J. Chelly, Paris, France
M. Raynauld, Tours, France
H. Van Bokhoven, Nijmegen, The Netherlands
J-P. Fryns, Leuven, Belgium
J. Gecz, Adelaide, Australia
Human Genome Laboratory (VIB)
Marijke Bauters
Guy Froyen
THANX !
top related