Table 1 Summary of clinical and molecular features of previously reported patients with constitutional 9q22 deletions and the present ones.

[28]

1y11m male

+ 3,8SD

> p 90

global delay

hypotonia

no falx calcification

right hydronephrosis

left multicystic kidney

left hand preaxial polydactyly

hypertelorism

frontal bossing

epicanthi

low nasal bridge

low-set ears

auricular pits

long philtrum

high palate

short, webbed neck

sacral dimple

with reservations to young age

aCGH (Agilent 180 chip) and FISH

9q22.3 de novo

2,44 Mb

deleted

nr

[14]

2 y 3 m male

> p97

p75-97

moderate MR,

wide cranial sutures,

open posterior fontanelle

submucous cleft palate,

pectus excavatum

epicanthic folds,

wide and short neck,

low nuchal hairline,

wide nasal bridge,

low-set and posteriorly rotated ears,

micrognathia, widely spaced nipples,

small teeth,

deep plantar grooves

with reservations to young age

aCGH at 1 Mb resolution

9q22.32q31.1 de novo

6,54-8,12 Mb

deleted

nr

[5]

3 y 9 m female

+2,2SD

+3,5SD

normal development, hypotonia, spasticity,

cleft lip-palate,

pigmented cyst on shoulder (ectopic meninx)

ASD

frontal bossing

epicanthic folds, broad eyebrows, synophrys,

c-a-l spot on legs and arm

yes

palmar & plantar pits

aCGH (Agilent 105A chip)

9q22.32 de novo

paternal

2.3 Mb

deleted

nr

[26, patient 1]

12 y male

-1,1SD

+1,7SD

moderate MR,

seizures/epilepsy

epicanthi

mouth small

upper lip thin

strabismus

yes

falx calcification,

frontal ganglioglioma, rib anomalies, odontogenic ceratocysts, palmar and plantar pits

FISH with BAC clones

9q21.33q22.33 de novo

15,33-16,04 Mb

deleted

nr

[26, patient 2]

23 y male

+1,9SD

+2,6SD

severe MR, seizures,

trigonocephaly, craniosynostosis,

cleft lip-palate

retinal detachement, cataract, glaucoma

double urethra

hypertelorism

yes

odonto-genic ceratocysts,

thyroid adenocarcinoma

FISH with BAC clones

9q21.33q31.1 de novo

18,08-18,54 Mb

deleted

nr

[27, restudy of patient 1 originally presented in 33]

50 y female

normal

macrocephaly

mild MR,

hypotonia,

"rib and bone anomalies"

kidney problems, one eye blind

frontal bossing,

palpebral fissures slant down,

epicanthi,

maxillary prognatism,,

dense eyebrows,

dental anomalies,

delayed dental eruption

yes

basocellular carcinomas,

jaw cysts, intracranial calcification, palmoplantar pits

quantitative multiplex fluorescent PCR, polymorphic markers, long-range PCR, sequencing

9q22.32q22.33 de novo

4,5 Mb

deleted

nr

[25, patient G10]

8 y male

nr

nr

severe MR,

epilepsy, hydrocephalus

inguinal hernia,

polydactyly

scoliosis

hypertelorism

yes

palmar & plantar pits

HR microarray

inv(9)(q21.2q33.1) = 9q22.32 92,934,973/92,945,040-98,137,216/98,141,889

5 Mb

deleted

nr

[16, patient G5, restudy of patient originally presented in 34]

12 y male

nr

>p97

severe MR, epilepsy,

dilated lateral ventricles,

thin corpus callosum, hydrocephalus

hydronephrosis, scoliosis

hypertelorism

epicanthi

webbed neck

yes

basal cell carcinoma,

palmar and plantar pits,

multiple jaw cysts

odonto-genic ceratocysts, calcification of falx and tentorium cerebelli

HR microarray

9q21.31q22.31 de novo 88,656,506/88,656,835-99,686,554/99,687,352

11 Mb

deleted

deleted

[17]

12 y female

nr

normal

severe MR, brain atrophy

laryngeal stenosis, pulmonary valve stenosi, pectus excavatum, kyphoscoliosis, hypoplastic clavicles

down-slanting palpebral fissures,

epicanthi, prognatism,

asymmetric palpebral fissures,

broad eyebrows,

synophrys

high forehead,

pointed chin

short neck,

c-a-l-spots

yes

aCGH

9q22.1q22.32 de novo

7,7 Mb

deleted

deleted

[6]

13 y female

nr

nr

MR,

ventriculomegaly

mild macroglossia

hypertelosim,

frontal bossing,

epicanthi,

ears posteriorly rotated,

teeth small,

prominent gingivae,

toenails hypoplastic,

mild hemihypertrophy

yes

mandibular cysts, plantar and palmar spots,

rhabdomyosarcoma,

Wilms tumor

karyotype,polymorphic markers at the PTCH1 region

9q22q32 de novo

paternal

nr

deleted

nr

[7, patient 1]

5 y male

+2,5SD

+2SD

severe MR

umbilical hernia,

pectus excavatum, trigonocephaly- craniosynostosis

epicanthi

mouth small

upper lip thin

ear pits

ears low set

ear lobules uplifted hyperlaxity,

short neck,

with reservations to young age

aCGH at 1 Mb resolution

9q22.32q22.33 de novo

paternal

< 6,5 Mb

not tested

nr

[7, patient 2]

8 y female

+2SD

>+3SD

severe MR, seizures

trigonocephaly

ventriculomegaly

thin corpus callosum

thyroglossal cyst with sternal fistula,

no dentition,

umbilical hernia,

pectus excavatum, kyphosis

epicanthi,

palpebral fissures slant down,

small mouth,

thin upper lip,

thick ears

indentation of ear lobules.

short neck

with reservations to young age

aCGH at 1 Mb resolution

9q22.32q22.33 de novo

paternal

< 6,5 Mb

not tested

nr

[27]

5 m male

p75-90

p90-97

MR, hypotonia

seizures

hydfrocephalus caused by compression by

cerebellar vermis

inguinal hernias,

PDA,

undescended testes,

high arched palate, postaxial polydactyly of left foot,

cervical ribs

hypertelorism, prognatism,

broad face and

forehead, broad

nasal bridge,

supraorbital ridges well developed

yes

HR karyotype, aCGH, FISH

9q22.32q31.3 de novo

paternal

12 Mb

deleted

nr

[15]

21 y male

+0,2SD

-1SD

mild MR

kyphosis, postaxial polydactyly,

mild pulmonary valve stenosis, inguinal hernias, undescended testes, hypodontia of permanent teeth, palate high arched,

uvula bifid, bilateral

nasal stenosis,

taurodonty of 2^nd molars

frontal bossing

epicanthi,

palperbral fissures slant down, prognatism, synophrys, hypotelorism, excess nuchal skin,

ears low-set and posteriorly rotated, nares anteverted,

lips thick,

face high

yes

calcification of cella turgica and falx cerebri, basal cell nevus carcinomas,

jaw cysts

HR karyotype, FISH with BAC clones

9q21.3q31 de novo

15.3-15.6 MB

deleted

deleted

[32]

29 y female

short

nr

poor vision,

telangiectatic nodule on skin

hemivertebra T5,

scoliosis,

elongated clavicle

hypotelorism,

ulnar deviation of hands

yes

multiple basaliomas,

calcification of falx, tentorium cerebri and cella turcica, mandibular cysts

karyotype

9q22.1q31.2

parents not available

nr

assumed deleted

nr

[4]

12 y female

nr

nr

mild MR,

bridging of cella turcica, broad cavum septi pellucid, dilated cerebral ventricles

hyperopia, deverticulum of the renal calyx, occult spina bifida L5-S4, pectus excavatum,

bilateral patellar dysplasia, unsual clavicles, exostosis of distal phalanx of thumb

thumbs, abnormal hypoplasia of maxilla

hypertelorism, biparietal bossing, epicanthi, palpebral fissures slant down, prognatism, synophrys,

webbed neck,

synophrys and broad eyebrows,

low midface,

broad nose tip,

low set, posteriorly rotated ears

yes

basalioma

basal cell nevi

trichoepithelioma

HR karyotype, FISH

9q22.32q33.2 de novo outside the maternal translocation

familial t(9;17)(q34.1p11.2)mat

nr

deleted

nr

[30, patient A]

age nr, female

nr

nr

MR

nr

karyotype, aCGH

9q21q22.1

nr

nr

deleted

[30, patient B]

age nr, female

nr

nr

MR

nr

karyotype, aCGH

9q22.1q31.2

nr

nr

deleted

[8]

6 y male

p50

>p97

severe MR

hypotony

PDA, severe scoliosis, fingers slender, 5^th finger camptodactyly, palate high arched, short metacarpals and distal phalanges

frontal bossing,

epicanthi,

palpebral fissures slant down,

ears low-set,

hypoplastic nostrils,

micrognarhia,

small nails

with reservations to young age

increasing nr of nevi,

sole pits

HR karyotype, FISH, genotyping

9q22.31q31.2 de novo

paternal

D9S303 ->D9S930

deleted

deleted

[3, patient 1]

15 y female

<p3

p75

MR, hydrocephalus with shunt, corpus callosum agenesis

inguinal hernias,

bilateral conductive hearing loss, ectopic eruption of incisors,

occult spina bifida T2-T3, scoliosis

frontal bossing, synophrys,

prognathism

yes

palmoplantar pits, bifid ribs

HR karyotype, RLFP polymorphisms

9q22q22 de novo

paternal

10-16 cM

deleleted

deleted

[3, patient 2]

26 y female

short

microcephaly

MR

PDA, CoA, anomalous right subclavian artery,

bilat conductive hearing loss

frontal bossing, hypertelorism, prognatism, prominent supraorbital ridges,

high palate

yes

multiple basal cell carcinomas, leiomyoma coli,

multiple bifid ribs

odontogenic ceratocysts,

ameloblastoma

HR karyotype, RLFP polymorphisms FISH

9q22q32 de novo

maternal t(ins[9][p22q32q22];16)(p22;q21) mat

22-39 cM

deleted

deleted

[9]

14 y male

<p3

<p3

severe MR

brachycephaly, dilated ventricles

undescended testes,

left pes equinovarus,

I partial I-IV toe syndactyly,

frontal bossing, hyperteloris,

epicanthi,

palpebral fissures slant down, broad eyebrows, wide mouth, thick lips, irregular dentition,

ears small, no ear lobes,

short neck, wide internipple distance, hypoplastic genitalia,

tapering fingers, small toes, medial deviation of toes

nr

karyotype

9q22q32 de novo

maternal

nr

nr

nr

[21]

15 m male

p25

p75

severe MR,

partial aplasia of corpus callosum,

dilatation of ventricles

laryngomalacia,

cleft palate,

PDA, abnormal aortic valve,

epiglottic dysplasia,

abnormal vocal cords

frontal bossing, palpebral fissures slant down, hypertrichosis, long eyelashes,

epicanthus inversus,

nose short, brodge depressed, nares upturned,

long philtrum,

small mouth, thin upper lip,

receding chin,

ears large and low set,

large lobules,

loose skin on cheeks

nr

karyotype (500 bands)

9q22q2207 de novo

nr

nr

nr

[2, patient 3]

7 m female

p90

p75

mild to moderate MR,

brachycephaly,

hydrocephalus

VSD,

PDA hallux valgus

hypertelorism,epicanthi,

synophrys,

ptosis,

philtrum short ears posteriorly rotated

nr

HR karyotype

9q22.3q31.1 de novo

paternal dir ins(4;9)(q33;q22.3q31.1) pat

nr

nr

nr

[35]

infant male

nr

nr

asymmetric ventricles, partial fusion of cerebellar hemispheres, polymicrogyria, delayed cerebellar neuronal migration, enlarged massa intermedia

cryptorchidism, focal glomerulosclerosis, accessory spleen, partial fusion of vertebrae D2 and D3, pectus excavatum,

irregular ribs

interphalangeal ankylosis

nr

karyotype

9q22q32 de novo

nr

nr

nr

[10]

3 m male

nr

nr

death at 3 months, seizures

duodenal atresia, malrotation,

Meckel diverticulum, multilobulated spleen, accessory spleens

renal dysplasia,

hydroureter

polydactyly of hand, syndactyly of feet

angulated clavicles

thorax asymmetric

palpebral fissures slant down, epicanthi, hypotelorism, hirsutism, short palpebral, fissures, depressed nasal bridge,

auditory canals narrow,

philtrum long

nr

unusual ribs,

karyotype, Q, C and R bands

9q22q32 de novo

maternal

nr

nr

nr

[1, patient 1]

14 y male

-1SD

0SD

severe MR,

epilepsy

hypertelorism,

palpebral fissures slant down, nose short, nares anteverted,

philtrum long, mild micrognathia

nr

karyotype with R bands

9q11q22 de novo

nr

nr

nr

Present case 3

37 y male

-1SD

-0,25SD

normal cognition,

dysarthria

grade IV vesicoureteral reflux, hydroureter and hypoplastic left kidney. funnel chest, three lower-most costal cartilages broadly fused

deepset and small toenails, palpebral fissures slant down, high bridged nose, narrow nares, long deep furrowed philtrum, ears with broad helices and uplifted lobuli, short 2^nd finger nails

no

aCGH

9q22.2q22.31 de novo

5,3Mb

not deleted

deleted

Present case 1

8,5 y female

0,1SD

+0,5SD

moderate MR,

dysarthria

short neck, slight ptosis on the right, downward slant of the palpebral fissures, narrow nose, small nares, long philtrum with a narrow deep groove, tented upper lip, ears with broad helices and uplifted lobuli. toe nails II-V bilaterally small

no

aCGH

9q22.2q22.31

paternal

5,3 Mb

not deleted

deleted

Present case 2

4 y female

-0,2SD

+1SD

moderate MR,

dysarthria

down slanting palpebral fissures, mild left side ptosis, narrow nares, uplifted ear lobuli and thick helices, long philtrum with a deep furrow, thin and tented upper lip.

no

aCGH

9q22.2q22.31

paternal

5,3Mb

not deleted

deleted