S2 Table. Genetic syndromes displaying various craniofacial abnormalities, used
to locate candidate genes for the study.
Syndrome
Symptoms
Prevalence
Genetic origin
Aarskog syndrome Distinct facial features, such as: rounded face, Rare
Mutations in FGDY1
(OMIM:100050)
underdeveloped mid-portion of the face (maxilla),
gene on X chromosome
small
[1]
nose
with
nostrils
tipped
forward
(anteverted), wide-set eyes, crease below the
lower lip (hypertelorism)
Alagille syndrome
Distinct facial features, such as broad forehead, 1 in 70,000
Mutations in JAG1 gene
(OMIM: 118450)
pointed mandible and bulbous tip of the nose and
[2]
in the fingers
Alfi's Syndrome
Mental retardation, trigonocephaly, mongoloid 1 in 5 million
Monosomy
9p
or
(OMIM: 158170)
eyes, wide flat nasal bridge, anteverted nostrils,
9p22.2-3 deletion [3]
long upper lip, cleft lip/palate, short neck, long
digits mostly secondary to long middle phalanges
Apert Syndrome
Various manifestations of craniosynostosis with Between 1 in Mutations
(OMIM: 101200)
cleft lip/palate.
65,000
in
FGFR2
to gene [4]
200,000
Beckwith-
Characteristic facial appearance and indentations Rare
Mutation or deletion of
Wiedemann
of the ears, a large tongue which may cause
genes H19, KCNQ1OT1
Syndrome
breathing, feeding or speech difficulties, one side
or CDKN1C in 11p15.5
(OMIM: 130650)
of the body grows more than the other
chromosomal region [57]
Cohen Syndrome
Abnormalities of the head, characteristic facial Rare
Mutations
(OMIM: 216550)
features including high-arched or wave-shaped
gene [8]
in
COH1
eyelids, a short philtrum, thick hair, and low
hairline
Cri-du-chat
Abnormal larynx and epiglottis which causes a 1 in 50,000 Mutations
Syndrome (OMIM: distinct sounding cry. The name literally means live births
123450).
Other “cry of the cat.” Other symptoms include mental
name: 5p deletion retardation,
syndrome
small
head
(microcephaly).
in
candidate
two
genes:
Semaphorine
F
(SEMA5A) and delta
Characteristic facial features at birth include a
catenin
large nasal bridge, round face, wide-spaced eyes,
potentially involved in
low-set ears, and a down-turned mouth. As the
cerebral
child gets older the facial features change and a
[9]
long, narrow face is more commonly observed
(CTNND2),
development
Crouzon Syndrome
Craniosynostosis
disorder
causing
secondary 1 in 60,000
(OMIM: 123500)
alterations of the facial bones and facial structure.
Mutations
in
FGFR2
gene [10,11]
Common features include hypertelorism, parrotbeaked nose, short upper lip, hypoplastic maxilla,
and a relative mandibular prognathism
Down Syndrome
(OMIM:
People with Down Syndrome have similar facial 1 in 600-1000 Extra
190685). features including a flattened facial profile, live
Other
copy
of
births. chromosome 21 in each
name: upward slanting eyes, small over-folded ears, flat Trisomy 21 is cell. Each person with
Trisomy 21
nose and small mouth with a protruding tongue. the
most Down syndrome may
They can also have low muscle tone, a shorter common
than typical neck, a single crease across the palm trisomy
have slightly different
seen symptoms
due
to
of the hand, heart defects, and varying levels of in live born variations
intellectual disability
individuals
in
chromosomal
abnormalities
(e.g.
Partial or full copy of
chromosome
21).
Several candidate genes
have been identified in
Down syndrome critical
region, such as DSCR1,
DSCR2,
DSCR3
and
DSCR4 [12] and SHH
[13]
Edward Syndrome. Small head (microcephaly), small jaw/mouth 1
Other
in
3000- Extra chromosome 18 in
name: (micrognathia), low-set malformed ears, cleft 8000
Trisomy 18
live each cell. Trisomy 18 is
lip/cleft palate, upturned nose, narrow eyelid births. 80% of the
folds, widely spaced eyes, clenched fists with people
second
most
with common trisomy seen in
overlapping fingers, mental retardation, growth this condition live born individuals
deficiency and other skeletal and organ anomalies
Floating-Harbor
are female
Short stature, a triangular shaped face with broad Rare
Mutations in SRCAP
Syndrome (OMIM: bulbous nose, long eyelashes, deep-set eyes and a
located
in
16p11.2
136140)
chromosomal
region
wide mouth with thin lips
[14].
Rubinstein-Taybi
syndrome
180849)
(OMIM:
shows
phenotypic overlap with
Floating-Harbor
syndrome and is caused
by
mutation
CREBBP
which
in
the
gene,
for
SRCAP
is
a
coactivator
Fragile
X Range of learning disorders, distinctive facial
A mutation in the FMR1
Syndrome
appearance with large ears and a long face,
gene located on the X
(OMIM:300624)
prominent jaws, speech and language problems
chromosome
[15,16].
Within this gene, there
is a region containing
the sequence “CGG”,
which
is
repeated
multiple
times.
Normally the sequence
is repeated no more than
55 times in the gene.
However,
Fragile
X
Syndrome occurs when
a person has more than
200 “CGG” repeats in
the FMR1 gene.
A person who has more
than 55 repeats, but less
than 200, is considered a
“pre-mutation
carrier.”
These individuals do not
have
Fragile
Syndrome
X
themselves
but are at risk of having
children affected with
the disorder since the
number of repeats could
expand
in
the
next
generation
Langer-Giedion
Short stature, small head, distinctive facial Rare
Deletion of 8q23.2 to
Syndrome
features including deep-set eyes, a bulbous nose,
q24.1
(OMIM:190350)
long narrow upper lip and missing teeth
region. Candidate gene
chromosomal
in this region: EXT1[17]
Noonan Syndrome Variable phenotype, which may change with age, 1 in 1,000 to Mutation in the PTPN11
(OMIM:163950)
many characteristics of which overlap those of the 2,500
live gene on chromosome
Turner syndrome. Short stature and mild mental births
12q24.1[18,19]
retardation are the main features of this syndrome.
Characteristic facial features including short
webbed neck and low-set posteriorly rotated ears
Pallister
Killian Coarse face with a high forehead, sparse hair on Rare
Mosaicism
for
Syndrome (OMIM: the scalp, an abnormally wide space between the
tetrasomy
of
601803)
chromosome 12p [20]
eyes, a fold of the skin over the inner corner of the
eyes and a flat nasal bridge with a highly arched
palate
Patau Syndrome
Other
Common features include: heart defects, small 1 in 10,000
name: heads (microcephaly), cleft lip and/or palate,
Trisomy 13
Trisomy of chromosome
13 [21]
small eyes that are close together, extra fingers
(polydactyly) and various skeletal abnormalities
Pfeiffer Syndrome
(OMIM:
Craniosynostosis, midface deficiency, cloverleaf 1 in 100,000
101600). skull, broad thumbs, broad great toes
Other
name:
Mutations in FGFR1,
FGFR2
and
FGFR3
in
FGFR2
[22,23]
CraniofacialSkeletalDermatologic
Dysplasia type 1, 2
and 3.
Saethre-Chotzen
Acrocephaly, asymmetry of the skull, low set 1 in 25,000 to Mutations
Syndrome
hairline, wide and tall forehead, thin, long pointed 50,000
(OMIM:101400).
nose, small low-set ears, cleft palate
Other
and TWIST1 [24-27]
name:
Acrocephalosyndac
tyly type III
Smith-Magenis
Abnormalities of the craniofacial area such as Rare
Syndrome (OMIM: brachycephaly, midface hypoplasia, small ears,
182290)
Mutations in RAI1 gene
[28,29]
broad nose and cleft palate. Overlapping features
with Potocki-Lupski syndrome
Treacher
Collins Various craniofacial abnormalities such as 1 in 25,000 to Mutations in
Syndrome
antimongoloid slant of the eyes, coloboma of the 50,000
gene [30-33]
(OMIM:154500)
lid, micrognathia, microtia and other deformity of
TCOF1
the ears, hypoplastic zygomatic arches and
macrostomia
Turner
Syndrome People with Turner Syndrome are females and 1 out of 2,500 Females with only one
(Monosomy X)
Velo-Cardio-Facial
typically have short stature, a webbed neck, heart girls
X
defects, swelling of the hands and feet, and
Potential involvement of
characteristic facial features
SHOX gene [35]
Highly variable phenotype with cleft palate, heart 1 out of 4000 Point
Syndrome (OMIM: abnormalities, typical faces and over 180 other live births
192430)
clinical findings
Waardenburg
Characterized by pigmentary abnormalities of the Rare
Syndrome (OMIM: hair, skin, eyes and facial structures, including
193500)
chromosome
[34].
mutations
TBX1 [36-38]
Mutations in PAX3 gene
[39].
broad nasal bridge
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