Table 1.

New disease genes in craniofacial malformations

Gene	Locus	Clinical disorder	OMIM # gene/disorder	Inheritance pattern	Major phenotypic features	Mechanism/pathway/comments	References
Craniosynostosis
CDC45	22q11.21	–	603 465/–	AR	Coronal suture synostosis, thin eyebrows, small ears, variable short stature	Peturbation of DNA replication, probable that some function remains	(3)
ERF	19q13.2	ERF-related craniosynostosis	611 888/600 775	AD	Mainly multisuture synostosis with postnatal onset, exorbitsm, midface hypoplasia, Chiari type I malformation, behavioural or learning difficulties	Haploinsufficiency; FGFR/ERK signalling	(4)
HUWE1	Xp11.22	–	300 697/–	XLD (n)	Multisuture or metopic craniosynostosis, learning difficulties	Unknown	(3)
TCF12	15q21.3	TCF12-related craniosynsotosis	600 480/615 314	AD	Coronal synostosis. May resemble Saethre-Chotzen syndrome with dysmorphic face, ears and minor limb anomalies. Other cases nonsyndromic, ∼50% clinical nonpenetrance	Haploinsufficiency; heterodimerization with TWIST1; RUNX2, BMP and FGFR signalling	(5)
ZIC1	3q24	ZIC1-related craniosynostosis	600 470/–	AD (n)	Severe bicoronal synostosis with learning difficulties	WNT signalling	(3)
Selected CL/P candidates
ABCB1	7q21.12	–	171 050/–	Complex	Non-syndromic orofacial cleft	Control of foetal exposure to foreign chemical substances	(6)
ADAMTS20	12q12	–	611 681/–	AR	CL/P and syndactyly	Uknown—Extracellular matrix processing?	(7)
FGFR2	10q26.13	–	176 943/–	Complex	NSCL/P	254 kb downstream of FGFR2; risk allele disrupts NC enhancer activity	(8)
GRHL3	1p36.11	Van der Woude syndrome 2	608 317/606 713	AD	CL/P, lip pits	Periderm development	(9)
NTN1	17p13.1	–	601 614/–	Complex	NSCL/P	Expressed in palatal shelves	(8)
NOG	17q22	–	602 991/–	Complex	NSCL/P	Risk allele shows significantly decreased enhancer activity	(8)
PAX7	1p36	–	167 410/–	Complex	NSCL/P	Involved in NC induction and specification of NC derivatives	(8,10)
FND
ZSWIM6	5q12.1	AFND	615 951/603 671	AD (n)	Frontonasal dysplasia with median cleft face and hypertelorism, agenesis of the corpus callosum, neurocognitive and motor delay, tibial hemimelia, preaxial polydactyly of feet	Gain-of-function; pathogenetic mechanism is unknown	(11)
SPECC1L	22q11.2	Opitz G/BBB	614 140/145 410	AD	Variable midline defects, hypertelorism, widow's peak, broad nasal bridge, CLP, and congenital heart defects and hypospadias	Haploinsufficiency; SPECC1L has role in cell adhesion and migration	(12)
Facial dysostoses
EIF4A3	17q25.3	RCPS	608 546/268 305	AR	Micrognathia with median cleft of the mandible, small mouth, CP, radial and tibial hypoplasia, learning and language difficulties	Reduced expression; component of exon junction complex; directly interacts with spliceosome components	(13)
EDN1	6p24.1	ACS; IQME	131 240/615 706 (ACS) & 612 798 (IQME)	AR (ACS)/AD (IQME)	ACS—Micrognathia, anomalies of temporomandibular joint and condyle, small mouth, prominent cheeks and question-mark ears IQME—question-mark ears	Loss-of-function; likely that residual function remains with AR mutations	(14)
EDNRA	4q31.22	Mandibulofacial dysostosis with alopecia	131 243/616 367	AD (n)	Micrognathia, dysplastic zygomatic arch, thickened malar bones, absent or hypoplastic lateral margin of the orbits, CP, short nose with broad nasal tip, dysplastic ears, hearing loss, sparse eyelashes and hypoplasia of the eyelids, alopecia	Possible gain-of-function	(15)
GSC	14q31.23	Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities (SAMS)	138 890/602 471	AR	Short stature, micrognathia, rhizomelic skeletal abnormalities including humeroscapular synostosis and abnormal pelvic ossification, hearing loss	Loss-of-function	(16)
POLR1A	2p11.2	Acrofacial dysostosis, Cincinnati type	616 404/–	AD	Variable mandibulofacial dysostosis, limb anomalies	Haploinsufficiency; ribosome biogenesis defect	(17)
SNRPB	20p13	Cerebrocostomandibular syndrome	182 282/117 650	AD (n)	Micrognathia, cleft soft palate, glossoptosis, posterior rib gaps	Mutations affect the recognition and inclusion of the premature termination codon-containing alternative exon; spliceosomal component	(18,19)
TGDS	13q32.1	Catel-Manzke syndrome	616 146/616 145	AR	Micrognathia, CP, bilateral hyperphalangy leading to index finger clinodactyly	Loss-of-function; likely that residual function remains; pathogenetic mechanism unknown	(20)
TXNL4A	18q23	Burn-McKeown syndrome	611 595/608 572	AR	CL/P, choanal atresia, sensorineural deafness, short palpebral fissures, lower eyelid coloboma, prominent nose with high nasal bridge	Loss-of-function; likely that residual function remains—combination of null and hypomorphic allele	(21)

AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant; (n), usually arises by new mutation.