X-gebonden verstandelijke beperking - NVAVGnvavg.nl/wp-content/uploads/2016/03/Van-Esch-X... ·...

X-gebonden verstandelijke

beperking

Hilde Van Esch


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


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

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.

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

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


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 ?


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)


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


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


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


Froyen G. et al, AJHG, 2008

Recurrent Xq25 dup involving STAG2

Kumar R. et al, HMG, 2015


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)


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 !

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