Clin Genet 2013: 83: 155–161Printed in Singapore. All rights reserved

© 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd

CLINICAL GENETICSdoi: 10.1111/j.1399-0004.2012.01862.x

Short Report

7q11.23 Microduplication: a recognizablephenotype

Dixit A, McKee S, Mansour S, Mehta SG, Tanteles GA, Anastasiadou V,Patsalis PC, Martin K, McCullough S, Suri M, Sarkar A. 7q11.23Microduplication: a recognizable phenotype.Clin Genet 2013: 83: 155–161. © John Wiley & Sons A/S. Published byBlackwell Publishing Ltd, 2012

Williams-Beuren syndrome is a well-known microdeletion syndrome witha recognizable clinical phenotype. The subtle phenotype of the reciprocalmicroduplication of the Williams-Beuren critical region has been describedrecently. We report seven further patients, and a transmitting parent, with7q11.23 microduplication. All our patients had speech delay, autisticfeatures and facial dysmorphism consistent with the published literature.We conclude that the presence of specific dysmorphic features, includingstraight, neat eyebrows, thin lips and a short philtrum, in our patients withspeech delay and autistic features provides further evidence that thechildren with 7q11.23 microduplication have a recognizable phenotype.

Conflict of interest

Nothing to declare.

A Dixita, S McKeeb,S Mansourc, SG Mehtad,GA Tantelese, V Anastasiadoue,PC Patsalise, K Martinf,S McCulloughg, M Suria

and A Sarkara

aDepartment of Clinical Genetics,Nottingham City Hospital, Nottingham,UK, bNorthern Ireland Regional GeneticsService, Belfast City Hospital, Belfast,UK, cSW Thames Regional GeneticsService, St George’s, University ofLondon, London, UK, dEast AnglianMedical Genetics Service,Addenbrooke’s Hospital, Cambridge, UK,eThe Cyprus Institute of Neurology andGenetics, Nicosia, Cyprus, fDepartmentof Cytogenetics, Nottingham CityHospital, Nottingham, UK, andgDepartment of Cytogenetics, BelfastCity Hospital, Belfast, UK

Key words: autism spectrum disorder –7q11.23 microduplication – speechdelay – Williams-Beuren critical region

Corresponding author: Dr Ajoy Sarkar,Department of Clinical Genetics, TheGables, Nottingham City Hospital,Hucknall Road, Nottingham NG51PB, UK.Tel.: +44 (0) 115 962 7728;fax: +44 (0) 115 962 8042;e-mail: ajoy.sarkar@nuh.nhs.uk

Received 27 October 2011; revised andaccepted for publication 21 February2012

The Williams-Beuren syndrome (WBS) (MIM 194050)is caused by a de novo 1.55 Mb microdeletion at7q11.23 and affects 1/7500 to 1/20,000 live births (1,2). Like other chromosomal microdeletions, the WBSmicrodeletion occurs due to non-allelic homologousrecombination (NAHR) between low copy repeats(LCRs) flanking the deleted region. Therefore, the exis-tence of the reciprocal microduplication syndrome isnot unexpected. The first microduplication of 7q11.23

was reported in 2005 (3) and a total of 29 cases havebeen reported to date (4–13). Speech delay and autis-tic features were identified in early publications anda recent paper (5) described the facial features in 14patients and reviewed previous publications to concludethat patients with 7q11.23 microduplication have a rec-ognizable facial phenotype.

We report seven patients and one transmitting parentwith 7q11.23 microduplication.

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Methods

Patients were identified during routine clinical inves-tigations in five different centres. Patients 4 and 5were identified through multiplex ligation-dependentprobe amplification (MLPA) (kits P245A1 and P064B2;MRC, Amsterdam, The Netherlands), and the remainingprobands through 0.56 Mb bacterial artificial chromo-some (BAC), and the 60k and 105k oligonucleotidearrays (all from BlueGnome Ltd., Cambridge, UK), 44koligonucleotide array (Agilent Technologies Inc., SantaClara, CA) or the GeneChip 6.0 single-nucleotide poly-morphism (SNP) genotyping array (Affymetrix Inc.,Santa Clara, CA). In patients 1, 2 and 7, additionalindependent fluorescence in situ hybridization (FISH)confirmation of the duplication was obtained using theVysis Williams syndrome probe. The same probe wasused for the diagnosis of patient 8 and her mother.In all cases, the hybridization signals obtained wereconsistent with duplications. MLPA was used for con-firmation in patient 3 (custom MLPA of South-EastThames molecular genetics laboratory) and patient 6(P064-MR1; MRC). The duplications in patients 4 and5 were originally identified using a general kit P245A1(MRC) and subsequently confirmed with the more spe-cific kit P064B2 (MRC). Patient 4 also had independentFISH confirmation of the duplication using the VysisWilliams syndrome probe.

Reynell Developmental Language Scales (patient 1)and Clinical Evaluation of Language Fundamentals-3, UK (patient 3) were used for formal speech andlanguage assessment. Patients 2 and 3 were assessedfor autism using the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic ObservationScale (ADOS). Patients 2 and 6 were assessed for atten-tion deficit hyperactivity disorder based on the ConnersParent Rating Scale. Patient 2 had detailed neuropsy-chological and language evaluation using WechslerPreschool and Primary Scale of Intelligence (WPPSI-IIIUK) and the Preschool Language Scale-3 (PLS-3 UK).

Clinical reports

The clinical features of our patients and comparisonwith the 29 individuals in published reports are depictedin Tables 1 and 2.

Speech delay and at least some autistic featureswere present in all our probands. Patient 1 commu-nicated mainly by grunting and pointing until 4 yearsof age. At the age of 6 years, he spoke only in veryshort phrases that were intelligible only to his parents.The oldest patient in our series (patient 6) is 16 yearsold, and health professionals have never witnessed anyform of vocalization. On last examination at 16 years,he used only minimal non-verbal gestures to reply todirect questioning. He is, however, reported to ver-bally converse with his parents, siblings and some closefriends. On formal speech and language assessment at35 months, patient 2 had two to three word phrases butthese were not intelligible. Neuropsychological evalu-ation at 4 years and 10 months showed his non-verbal

cognitive performance to be at the 93rd centile on theWPPSI-III UK. On the PLS-3 UK, he had a low aver-age score for understanding of language (86-expectedrange 85–115). The expressive communication sectionof PLS-3 UK could not be scored as speech errors madeit difficult to interpret his responses. He used gesturing,in preference to language or pictures, to support hisspeech intelligibility. As he had difficulty in coordinat-ing sounds and planning oral movements, it was sug-gested that he had developmental verbal dyspraxia. Theuse of non-verbal gestures to support the intelligibilityof speech has also been observed in three of the sevencases reported by Berg et al. (6) and is reminiscent ofdevelopmental verbal dyspraxia (MIM 602081) (14).

Most patients had some motor delay as well, butformal cognitive testing in patients 2 and 3 revealednon-verbal cognitive performances to be in the normalrange.

The dysmorphic features shared by most patientsincluded broad forehead, high, broad nose, straight eye-brows, short philtrum and thin upper lip (Table 2).Patient 6 had some unusual growth and phenotypic fea-tures. His head circumference was 52 cm (−2 to −3SD), height was 146 cm (−3 to −4 SD) and weightwas 36 kg (−3 to −4 SD). His span to height ratiowas 1. His bone age was 3 years delayed comparedto his chronological age. Apart from features listed inTable 2, he had additional dysmorphism in the form ofthickened, straight eyebrows with synophrys and hyper-telorism with down-slanting palpebral fissures and along, tubular nose (Fig. 1k,l).

Cleft lip and/or palate have been reported in threeprevious cases (6, 11). Ventricular dilatation on brainimaging has been reported by several authors (5–7, 11,13). Most cases are due to mild and non-specific dilata-tion of lateral ventricles. Other non-specific abnormali-ties have also been noted on brain magnetic resonanceimaging in several cases. Undescended testes have beenreported in four previous patients (5). Congenital car-diac defects have been reported in 6/29 cases (5, 11),but no other congenital anomalies have been reportedconsistently.

Three out of our seven probands had a birth weightabove the 91st centile including patient 7 whose birthweight was >99.6th centile. Three patients had a headcircumference above 91st centile and a further patient’shead circumference was at 75th centile. Six of 14patients in the Van der Aa et al. series (5) also hadhead circumference above 90th centile.

Patient 8 is the mother of patient 7 and was evaluatedfollowing her daughter’s diagnosis. She has a history oflearning difficulties and attended a special school. Shehas been assessed as having an IQ of 50 but has normalspeech and no history of speech or motor delay. Thereis no history of autism or behavioural difficulties, butshe is very shy. She lives with her mother and is unableto care for her daughter independently. Her height was159 cm (25th centile), weight 88.7 kg (99.6th centile),and head circumference 55.5 cm (25th–50th centile).She had inherited the duplication from her own mother;the duplication has therefore been shown to be present

156

7q11.23 Microduplication

Tabl

e1.

Gro

wth

para

met

ers

and

deve

lopm

enta

lfea

ture

sof

patie

nts

1–7

and

com

paris

onw

ithpa

tient

sre

port

edin

liter

atur

e(5

,11,

13)

Feat

ure

Pat

ient

1P

atie

nt2

Pat

ient

3P

atie

nt4

Pat

ient

5P

atie

nt6

Pat

ient

7P

rese

ntst

udy

Indi

vidu

als

inlit

erat

ure

Siz

eof

dupl

icat

ion

(Mb)

1.5

1.2

1.44

2N

Aa

NA

a2.

554

––

Inhe

ritan

ceU

ncer

tain

bD

eno

voD

eno

voD

eno

voU

ncer

tain

bD

eno

voM

ater

nal

––

Gro

wth

Age

atex

amin

atio

n(y

ear)

53 / 4

63 / 4

91 / 2

21 / 2

23 / 4

163

––

Wei

ght(

cent

ile)

50th

25th

50th

91st

50th

<0.

4th

50th

–75t

h–

–H

eigh

t(ce

ntile

)25

th50

th25

th2n

d9t

h�

0.4t

h9t

h–2

5th

––

Hea

dci

rcum

fere

nce

(cen

tile)

91st

25th

–50t

h90

th75

th9t

h–2

5th

0.4t

h91

st–9

8th

––

Birt

hw

eigh

t(ce

ntile

)2n

d9t

h91

st–9

8th

91st

–98t

h25

th9t

h–2

5th

>99

.6th

––

Neu

rod

evel

op

men

tal

feat

ures

Spe

ech

dela

yY

YY

YY

YY

7/7

29/2

9E

xpre

ssiv

eE

xpre

ssiv

eN

asal

spee

chre

cept

ive

Exp

ress

ive

and

rece

ptiv

eE

xpre

ssiv

ean

dre

cept

ive

Sev

ere

expr

essi

veE

xpre

ssiv

e–

–

Aut

istic

feat

ures

YY

YY

YY

Y7/

711

/29

Mot

orG

ross

mot

orde

lay

Gro

ssan

dfin

em

otor

dela

y–

Gro

ssm

otor

dela

yG

ross

mot

orde

lay

Mild

mot

orde

lay

Gro

ssm

otor

dela

y–

–

Beh

avio

ural

prob

lem

sN

Agg

ress

ion,

AD

HD

Anx

iety

Tric

hoph

agy

and

pica

YA

nxie

ty,A

DH

DA

ggre

ssio

n–

–E

pile

psy

NN

NN

NN

N0/

76/

29H

ypot

onia

YY

NY

YN

Y5/

715

/21

Join

tlax

ityY

YM

ildY

YY

Y7/

76/

27M

RIb

rain

Ben

ign

hydr

ocep

halu

sN

AN

AN

AN

AP

rom

inen

tV

ircho

w-R

obin

spac

es

NA

2/2

–

Con

geni

tala

nom

aly

NC

left

pala

teN

NN

Und

esce

nded

test

esN

2/7

–

Oth

er–

––

Ser

ous

OM

,GE

RD

Ser

ous

OM

––

––

AD

HD

,att

entio

nde

ficit

hype

ract

ivity

diso

rder

;GE

RD

,gas

troe

soph

agea

lrefl

uxdi

seas

e;M

RI,

mag

netic

reso

nanc

eim

agin

g;N

,no;

NA

,not

appl

icab

le;O

M,O

titis

med

ia;Y

,yes

.aD

iagn

osed

byM

LPA

.bO

nly

mot

her

test

ed,p

ater

nals

ampl

eun

avai

labl

e.

157

Dixit et al.

Table 2. Facial features of patients 1–7 and comparison with patients reported in literature (5, 11, 13)

Feature Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7Presentstudy

Individualsin literature

Broad forehead Y N Y Y Y Y Y 6/7 12/26High, broad nose Y N Y Y N Y Y 5/7 16/26Low-set ears N N Y Y N N Y 3/7 9/26Posteriorly rotated ears Y Y N Y N Y N 4/7 9/24Other ear abnormality Prominent

earOverfolded

helicesN Prominent

earN Prominent

earOverfolded

helices5/7 8/15

Deep-set eyes N Y Y N Y N Y 4/7 10/25Hypertelorism Y Y N Y N Y Y 5/7 6/24Straight brows Y Y Y Y Y Y Y 7/7 14/25Short philtrum Y Y Y Y Y N Y 6/7 12/25Thin upper lip Y Y Y N N Y Y 5/7 19/25

Y, yes; N, no.

in three generations in this family. The grandmother haslow-normal intelligence, normal speech and worked ina food packing factory. Other family members have notyet been evaluated.

Discussion

Expressive speech delay is the hallmark of 7q11.23microduplication with autistic features also present ina significant proportion of patients. This suggests thepresence of one or more dosage-sensitive genes in thisregion involved in speech and language development.Triplication of the WBS critical region has been iden-tified in two unrelated patient with severe expressivespeech delay (15, 16).

Subtle dysmorphic features have been reported inmost patients with 7q11.23 microduplication. Van derAa et al. (5) described the facial phenotype of 14 casesand analysed the photographs of previously publishedcases. They concluded that patients with 7q11.23microduplication have a recognizable face with straight,neatly placed eyebrows, a high, broad nose and thinupper lip as the most frequent findings. Other featuresincluded deep-set eyes, short philtrum and a prominentforehead. The facial phenotype of our patients stronglysupports these findings (Table 2) and provides furtherevidence that these patients have a recognizable facialgestalt.

Patient 1 was originally referred by his paediatricianfor molecular testing for hereditary sensory and motorneuropathy at the age of 5 years as he was hypotonicand thought to have absent lower limb tendon reflexes.A probe from the 7q11.23 region was used as a controlin the MLPA kit, and a duplication of this region wasidentified. Array comparative genomic hybridization(CGH) confirmed duplication of the WBS criticalregion. This serendipitous diagnosis mirrors that of thefirst patient described with 7q11.23 microduplicationin literature who, while being tested by real-timePCR for velocardiofacial syndrome, was found to haveduplication of markers in the WBS critical region (3).

Five of our seven probands were either diagnosedby arrayCGH or SNP array (Fig. 2). While three

patients had a 1.2–1.5 Mb duplication that is recipro-cal to the region deleted in WBS, two patients had alarger duplication. The centromeric breakpoint of theduplication of patient 7 (4 Mb) at 72,390,000 (NCBIBuild 36) matches well-characterized WBS LCRs, butthe telomeric breakpoint at 76,407,000 is approximately2.5 Mb distal to the usual WBS LCRs resulting in dupli-cation of several additional genes including MDH2,YWHAG, HSPB1, ZP3, SRCRB4D and DTX2, with thelast apparently duplicated gene being POMZP3. Theduplication of patient 6 was also larger than usual at2.55 Mb with the centromeric and telomeric break-points at 72,338,379 and 74,882,474, respectively, onNCBI Build 36. There are additional LCRs in theregions corresponding to the telomeric breakpoints ofpatients 6 and 7 [UCSC genome browser (17) seg-mental duplication track (accessed on October, 2011)]and it is likely that the larger duplications are alsoNAHR-mediated. Most patients with WBS microdu-plication in literature, including all 14 patients in themost recent series (5), have the typical 1.4–1.5 Mbduplication. Despite the larger sized duplication, patient7 did not show any additional or more severe fea-tures in comparison with the other patients in ourseries. At least one other patient with a similar atyp-ical larger duplication has been reported in the past,who did not have any additional features either (6).Patient 6 has short stature, but this may represent thevariability of the growth phenotype of the 7q11.23microduplication.

One instance of parental transmission was identified(patients 7 and 8). Patient 8 had some learning dif-ficulties but normal speech and no history of speechdelay. The microduplication has been reported to occuras a result of parental transmission in several previ-ously reported cases (5, 6). Most transmitting parentshave some neurobehavioural problems but some parentswith normal speech and cognitive abilities have alsobeen reported (6). It is not yet clear if the neurocogni-tive problems become less apparent with age in somepatients with 7q11.23 microduplication or whether theidentified adults represent the milder end of the pheno-typic spectrum.

158

7q11.23 Microduplication

(a)

(e)

(m) (n) (o) (p)

(i) (j) (k) (l)

(f) (g) (h)

(b) (c) (d)

Fig. 1. Photographs of patients 1–8 showing facial phenotype: (a, b) patient 1, (c, d) patient 2, (e, f) patient 3, (g, h) patient 4, (i, j) patient 5,(k, l) patient 6, (m, n) patient 7, and (o, p) patient 8.

Interestingly, WBS and 7q11.23 microduplicationaffect the phenotype in opposite ways. While childrenwith WBS usually have a short upturned nose, longphiltrum with full lips and a relative strength in expres-sive language, children with the microduplication havea high, broad nose, short philtrum with thin lips andexpressive speech delay with deficits in social inter-action. Like other reciprocal deletion/duplication syn-dromes, phenotype of the 7q11.23 microduplicationis milder and more variable than the correspondingmicrodeletion syndrome. High prevalence of autisticfeatures is another trait that our patients share withother microduplication syndromes. The variable and

less distinctive phenotype is the most likely explanationfor under-diagnosis and explains the paucity of casesin the published literature. More cases are likely to beidentified with the increased use of arrayCGH in theinvestigation of children with developmental and neu-robehavioural problems. A recent study has identified asignificant association between autism spectrum disor-der and 7q11.23 microduplication (18).

In conclusion, our patients provide further evidencethat the clinical phenotype of 7q11.23 microduplicationis recognizable. The facial phenotype is subtle but dis-tinct and in the presence of speech delay with or without

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Fig. 2. Comparison of the sizes of duplications (identified by arrayCGH) in patients 1, 2, 3, 6 and 7 shown in light grey. Minimum sizes ofduplications in patients 4 and 5 (identified by multiplex ligation-dependent probe amplification) shown in dark grey.

autistic features, should enable the astute clinician tomake this diagnosis.

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