S1 Table. Genetic syndromes displaying various craniofacial abnormalities, used to locate candidate genes for the study

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S1 Table. Genetic syndromes displaying various craniofacial abnormalities, used to locate candidate genes for the study.




Genetic origin

Aarskog syndrome (OMIM:100050)

Distinct facial features, such as: rounded face, underdeveloped mid-portion of the face (maxilla), small nose with nostrils tipped forward (anteverted), wide-set eyes, crease below the lower lip (hypertelorism)


Mutations in FGDY1 gene on X chromosome [1]

Alagille syndrome

(OMIM: 118450)

Distinct facial features, such as broad forehead, pointed mandible and bulbous tip of the nose and in the fingers

1 in 70,000

Mutations in JAG1 gene [2]

Alfi's Syndrome

(OMIM: 158170)

Mental retardation, trigonocephaly, mongoloid eyes, wide flat nasal bridge, anteverted nostrils, long upper lip, cleft lip/palate, short neck, long digits mostly secondary to long middle phalanges

1 in 5 million

Monosomy 9p or 9p22.2-3 deletion [3]

Apert Syndrome

(OMIM: 101200)

Various manifestations of craniosynostosis with cleft lip/palate.

Between 1 in 65,000 to 200,000

Mutations in FGFR2 gene [4]

Beckwith-Wiedemann Syndrome

(OMIM: 130650)

Characteristic facial appearance and indentations of the ears, a large tongue which may cause breathing, feeding or speech difficulties, one side of the body grows more than the other


Mutation or deletion of genes H19, KCNQ1OT1 or CDKN1C in 11p15.5 chromosomal region [5-7]

Cohen Syndrome

(OMIM: 216550)

Abnormalities of the head, characteristic facial features including high-arched or wave-shaped eyelids, a short philtrum, thick hair, and low hairline


Mutations in COH1 gene [8]

Cri-du-chat Syndrome (OMIM: 123450). Other name: 5p deletion syndrome

Abnormal larynx and epiglottis which causes a distinct sounding cry. The name literally means “cry of the cat.” Other symptoms include mental retardation, small head (microcephaly). Characteristic facial features at birth include a large nasal bridge, round face, wide-spaced eyes, low-set ears, and a down-turned mouth. As the child gets older the facial features change and a long, narrow face is more commonly observed

1 in 50,000 live births

Mutations in two candidate genes: Semaphorine F (SEMA5A) and delta catenin (CTNND2), potentially involved in cerebral development [9]

Crouzon Syndrome

(OMIM: 123500)

Craniosynostosis disorder causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism

1 in 60,000

Mutations in FGFR2 gene [10,11]

Down Syndrome

(OMIM: 190685). Other name: Trisomy 21

People with Down Syndrome have similar facial features including a flattened facial profile, upward slanting eyes, small over-folded ears, flat nose and small mouth with a protruding tongue. They can also have low muscle tone, a shorter than typical neck, a single crease across the palm of the hand, heart defects, and varying levels of intellectual disability

1 in 600-1000 live births. Trisomy 21 is the most common trisomy seen in live born individuals

Extra copy of chromosome 21 in each cell. Each person with Down syndrome may have slightly different symptoms due to variations 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. Other name: Trisomy 18

Small head (microcephaly), small jaw/mouth (micrognathia), low-set malformed ears, cleft lip/cleft palate, upturned nose, narrow eyelid folds, widely spaced eyes, clenched fists with overlapping fingers, mental retardation, growth deficiency and other skeletal and organ anomalies

1 in 3000-8000 live births. 80% of people with this condition are female

Extra chromosome 18 in each cell. Trisomy 18 is the second most common trisomy seen in live born individuals

Floating-Harbor Syndrome (OMIM: 136140)

Short stature, a triangular shaped face with broad bulbous nose, long eyelashes, deep-set eyes and a wide mouth with thin lips


Mutations in SRCAP located in 16p11.2 chromosomal region [14]. Rubinstein-Taybi syndrome (OMIM: 180849) shows phenotypic overlap with Floating-Harbor syndrome and is caused by mutation in the CREBBP gene, for which SRCAP is a coactivator

Fragile X Syndrome (OMIM:300624)

Range of learning disorders, distinctive facial appearance with large ears and a long face, prominent jaws, speech and language problems

A mutation in the FMR1 gene located on the X 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 X Syndrome 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 Syndrome (OMIM:190350‎)

Short stature, small head, distinctive facial features including deep-set eyes, a bulbous nose, long narrow upper lip and missing teeth


Deletion of 8q23.2 to q24.1 chromosomal region. Candidate gene in this region: EXT1[17]

Noonan Syndrome (OMIM:163950)

Variable phenotype, which may change with age, many characteristics of which overlap those of the Turner syndrome. Short stature and mild mental retardation are the main features of this syndrome. Characteristic facial features including short webbed neck and low-set posteriorly rotated ears

1 in 1,000 to 2,500 live births

Mutation in the PTPN11 gene on chromosome 12q24.1[18,19]

Pallister Killian Syndrome (OMIM: 601803)

Coarse face with a high forehead, sparse hair on the scalp, an abnormally wide space between the eyes, a fold of the skin over the inner corner of the eyes and a flat nasal bridge with a highly arched palate


Mosaicism for tetrasomy of chromosome 12p [20]

Patau Syndrome

Other name: Trisomy 13

Common features include: heart defects, small heads (microcephaly), cleft lip and/or palate, small eyes that are close together, extra fingers (polydactyly) and various skeletal abnormalities

1 in 10,000

Trisomy of chromosome 13 [21]

Pfeiffer Syndrome

(OMIM: 101600). Other name: Craniofacial-Skeletal-Dermatologic Dysplasia type 1, 2 and 3.

Craniosynostosis, midface deficiency, cloverleaf skull, broad thumbs, broad great toes

1 in 100,000

Mutations in FGFR1, FGFR2 and FGFR3 [22,23]

Saethre-Chotzen Syndrome (OMIM:101400). Other name: Acrocephalosyndactyly type III

Acrocephaly, asymmetry of the skull, low set hairline, wide and tall forehead, thin, long pointed nose, small low-set ears, cleft palate

1 in 25,000 to 50,000

Mutations in FGFR2 and TWIST1 [24-27]

Smith-Magenis Syndrome (OMIM: 182290)

Abnormalities of the craniofacial area such as brachycephaly, midface hypoplasia, small ears, broad nose and cleft palate. Overlapping features with Potocki-Lupski syndrome


Mutations in RAI1 gene [28,29]

Treacher Collins Syndrome (OMIM:154500)

Various craniofacial abnormalities such as antimongoloid slant of the eyes, coloboma of the lid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches and macrostomia

1 in 25,000 to 50,000

Mutations in TCOF1 gene [30-33]

Turner Syndrome (Monosomy X)

People with Turner Syndrome are females and typically have short stature, a webbed neck, heart defects, swelling of the hands and feet, and characteristic facial features

1 out of 2,500 girls

Females with only one X chromosome [34]. Potential involvement of SHOX gene [35]

Velo-Cardio-Facial Syndrome (OMIM: 192430)

Highly variable phenotype with cleft palate, heart abnormalities, typical faces and over 180 other clinical findings

1 out of 4000 live births

Point mutations in TBX1 [36-38]

Waardenburg Syndrome (OMIM: 193500)

Characterized by pigmentary abnormalities of the hair, skin, eyes and facial structures, including broad nasal bridge


Mutations in PAX3 gene [39].


1. Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns J-P, et al. (2003) Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Eur J Hum Genet 12: 16-23.

2. Kamath BM, Stolle C, Bason L, Colliton RP, Piccoli DA, et al. (2002) Craniosynostosis in Alagille syndrome. Am J Med Genet 112: 176-180.

3. Kawara H, Yamamoto T, Harada N, Yoshiura K, Niikawa N, et al. (2006) Narrowing candidate region for monosomy 9p syndrome to a 4.7-Mb segment at 9p22.2-p23. Am J Med Genet A 140: 373-377.

4. Andreou A, Lamy A, Layet V, Cailliez D, Gobet F, et al. (2006) Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (Pro253Arg). Am J Med Genet A 140: 2245-2247.

5. Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, et al. (1996) An imprinted gene p57KIP2 is mutated in Beckwith–Wiedemann syndrome. Nat Gen 14: 171-173.

6. Catchpoole D, Smallwood AV, Joyce JA, Murrell A, Lam W, et al. (2000) Mutation analysis of H19 and NAP1L4 (hNAP2) candidate genes and IGF2 DMR2 in Beckwith-Wiedemann syndrome. J Med Genet 37: 212-215.

7. Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, et al. (2002) Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet 11: 1317-1325.

8. Kolehmainen J, Wilkinson R, Lehesjoki AE, Chandler K, Kivitie-Kallio S, et al. (2004) Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet 75: 122-127.

9. Wu Q, Niebuhr E, Yang H, Hansen L (2005) Determination of the 'critical region' for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR. Eur J Hum Genet 13: 475-485.

10. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, et al. (1994) Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8: 98-103.

11. Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, et al. (2000) Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 66: 768-777.

12. Nakamura A, Hattori M, Sakaki Y (1997) A novel gene isolated from human placenta located in Down syndrome critical region on chromosome 21. DNA Res 4: 321-324.

13. Roper RJ, Baxter LL, Saran NG, Klinedinst DK, Beachy PA, et al. (2006) Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice. Proc Natl Acad Sci U S A 103: 1452-1456.

14. Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C, et al. (2012) Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. Am J Hum Genet 90: 308-313.

15. Machado-Ferreira Mdo C, Costa-Lima MA, Boy RT, Esteves GS, Pimentel MM (2004) Premature ovarian failure and FRAXA premutation: Positive correlation in a Brazilian survey. Am J Med Genet A 126A: 237-240.

16. Chonchaiya W, Au J, Schneider A, Hessl D, Harris SW, et al. (2012) Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder. Hum Genet 131: 581-589.

17. McBrien J, Crolla JA, Huang S, Kelleher J, Gleeson J, et al. (2008) Further case of microdeletion of 8q24 with phenotype overlapping Langer-Giedion without TRPS1 deletion. Am J Med Genet A 146A: 1587-1592.

18. Kondoh T, Ishii E, Aoki Y, Shimizu T, Zaitsu M, et al. (2003) Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report. Eur J Pediatr 162: 548-549.

19. Croonen EA, van der Burgt I, Kapusta L, Draaisma JM (2008) Electrocardiography in Noonan syndrome PTPN11 gene mutation--phenotype characterization. Am J Med Genet A 146: 350-353.

20. Izumi K, Conlin LK, Berrodin D, Fincher C, Wilkens A, et al. (2012) Duplication 12p and Pallister-Killian syndrome: a case report and review of the literature toward defining a Pallister-Killian syndrome minimal critical region. Am J Med Genet A 158A: 3033-3045.

21. Jønch AE, Larsen LG, Pouplier S, Nielsen K, Brøndum‐Nielsen K, et al. (2012) Partial duplication of 13q31. 3–q34 and deletion of 13q34 associated with diaphragmatic hernia as a sole malformation in a fetus. Am J Med Genet A 158: 2302-2308.

22. Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, et al. (1996) Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet 14: 174-176.

23. Muenke M, Schell U, Hehr A, Robin NH, Losken HW, et al. (1994) A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet 8: 269-274.

24. Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, et al. (1997) Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet 15: 36-41.

25. el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, et al. (1997) Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet 15: 42-46.

26. Bourgeois P, Bolcato-Bellemin AL, Danse JM, Bloch-Zupan A, Yoshiba K, et al. (1998) The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome. Hum Mol Genet 7: 945-957.

27. El Ghouzzi V, Legeai-Mallet L, Benoist-Lasselin C, Lajeunie E, Renier D, et al. (2001) Mutations in the basic domain and the loop-helix II junction of TWIST abolish DNA binding in Saethre-Chotzen syndrome. FEBS Lett 492: 112-118.

28. Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH (2003) Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33: 466-468.

29. Girirajan S, Elsas LJ, 2nd, Devriendt K, Elsea SH (2005) RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet 42: 820-828.

30. Haworth KE, Islam I, Breen M, Putt W, Makrinou E, et al. (2001) Canine TCOF1; cloning, chromosome assignment and genetic analysis in dogs with different head types. Mamm Genome 12: 622-629.

31. Meyer T, Teruel MN (2003) Fluorescence imaging of signaling networks. Trends Cell Biol 13: 101-106.

32. Masotti C, Armelin-Correa LM, Splendore A, Lin CJ, Barbosa A, et al. (2005) A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction. Gene 359: 44-52.

33. Hunemeier T, Salzano FM, Bortolini MC (2009) TCOF1 T/Ser variant and brachycephaly in dogs. Anim Genet 40: 357-358.

34. Sybert VP, McCauley E (2004) Turner's syndrome. N Engl J Med 351: 1227-1238.

35. Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, et al. (2000) The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet 9: 695-702.

36. Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, et al. (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362: 1366-1373.

37. Guo C, Sun Y, Zhou B, Adam RM, Li X, et al. (2011) A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J Clin Invest 121: 1585-1595.

38. Merscher S, Funke B, Epstein JA, Heyer J, Puech A, et al. (2001) TBX1 is responsible for cardiovascular defects in Velo-Cardio-Facial/DiGeorge syndrome. Cell 104: 619-629.

39. Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, et al. (1993) Mutations in the Paired Domain of the Human Pax3 Gene Cause Klein-Waardenburg Syndrome (Ws-Iii) as Well as Waardenburg Syndrome Type-I (Ws-I). Am J Hum Genet 52: 455-462.

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