Table 4.

Genes of Interest in the Differential Diagnosis of Oral-Facial-Digital Syndrome Type I

Gene(s)DisorderMOIDistinctive Features / Comment
C2CD3 C2CD3-related OFD
(OMIM 615948) /
JS-OFD		ARSevere microcephaly & ID. Brain MRI shows vermis hypoplasia & MTS.
CEP164 CEP164-related OFD 1ARPostaxial polydactyly, hypotonia, cerebral malformations, hydronephrosis, & urogenital abnormalities. (CEP164 is also assoc w/nephronophthisis.)
CLUAP1 CLUAP1-related
JS-OFD 2		AREpiglottis cleft, short limbs, ID. Brain MRI shows MTS. One individual reported to date.
CPLANE1
(C5orf42)		CPLANE1-related OFD (OMIM 277170) / JS-OFDARPolydactyly (particularly central) & cerebellar malformations. Renal agenesis & dysplasia have been described. Brain MRI may show MTS. 3
DDX59 DDX59-related OFD (OMIM 174300)ARPolydactyly & median cleft lip only. Hyperplastic frenula reported in 1 person.
FAM149B1 FAM149B1-related JS (OMIM 618763)ARMacrocephaly. Brain MRI shows MTS. Reported in 1 family to date.
IFT57 IFT57-related OFD (OMIM 617927)ARShort stature, skeletal dysplasia, & brachymesophalangia
INTU INTU-related OFD (OMIM 617926)ARCardiac defects, deafness, polydactyly. (Also assoc w/INTU-related SRPS [OMIM 617925].)
KIAA0753
(OFIP)		KIAA0753-related OFD (OMIM 617127)ARPolydactyly (particularly postaxial). Brain MRI shows vermis hypoplasia & MTS. (Also assoc w/KIAA0753-related short-rib thoracic dysplasia [OMIM 619479] & JS [OMIM 619476].)
NEK1 NEK1-related OFD2 (Mohr syndrome) 4ARDental agenesis, maxillary hypoplasia, conductive hearing loss, & bilateral tortuosity of retinal veins. (Also assoc w/NEK1-related SRPS [OMIM 263520].)
SCLT1 SCLT1-related OFD 4ARMicrocephaly, coloboma, choanal atresia, congenital heart disease, agenesis of corpus callosum
SCNM1 SCNM1-related OFD (OMIM 620107)ARPostaxial polydactyly, tongue nodules, abnormalities of incisors, cleft palate, & retrognathia
TBC1D32 TBC1D32-related OFD 4ARMicrocephaly, coloboma, choanal atresia, agenesis of corpus callosum, congenital heart disease, & seizures. 1 person described to date.
TCTN1 TCTN1-related JSARPolydactyly & cerebellar malformations
TCTN3 TCTN3-related OFD4
(Mohr-Majewski)
(OMIM 258860) /
JS-OFD		ARTibial involvement & polydactyly are primary manifestations. Micrognathia. Other findings incl pectus excavatum & short stature.
TMEM107 TMEM107-related OFD (OMIM 617563) / JS-OFDARPostaxial polydactyly. ID. Brain MRI shows vermis hypoplasia & MTS.
TMEM138 TMEM138-related OFD 4ARBrain MRI shows vermis hypoplasia & MTS. (TMEM138 is also assoc w/JS.)
TMEM216 TMEM216-related OFD 4 / JS-OFDARPolydactyly, nephronophthisis, & cystic kidneys. Brain MRI shows MTS.
TMEM231 TMEM231-related OFD 4ARBrain MRI shows vermis hypoplasia & MTS. (TMEM231 is also assoc w/JS.)
TOPORS TOPORS-related OFD 1ARPostaxial polydactyly, hypotonia, cerebral malformations, & urogenital abnormalities. (TOPORS is also assoc w/retinitis pigmentosa.)
B9D1
B9D2
CC2D2A
CEP290
KIF14
MKS1
NPHP3
RPGRIP1L
TCTN2
TMEM107
TMEM216
TMEM231
TMEM67
TXNDC15 		Meckel syndrome (OMIM PS249000)ARCNS malformation (posterior encephalocele, cerebral & cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, & early demise. Additional findings incl cleft lip & palate, ambiguous genitalia, microcephaly, & microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, & corneal dysgenesis.
ALG5
ALG9
DNAJB11
GANAB
IFT140
PKD1
PKD2 		Autosomal dominant polycystic kidney disease (ADPKD)ADADPKD has been diagnosed in some persons who later were found to have OFD1. 5 In ADPKD, cysts develop from tubules; in OFD1, cysts develop from both tubules & glomeruli (imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD & other cystic renal disorders). OFD1 cysts are said to be smaller & more uniform in size than in ADPKD & kidneys are not as enlarged or malformed in OFD1. ADPKD is not assoc w/oral, facial, digital, or brain abnormalities.
PRKACB Cardioacrofacial dysplasia 2 (OMIM 619143)ADPostaxial polydactyly, brachydactyly, oral frenulae, dental abnormalities, ID, & seizures. Additional findings incl long thorax & heart defects.

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; ID = intellectual disability; JS = Joubert syndrome; JS-OFD = Joubert syndrome with oral-facial-digital features; MOI = mode of inheritance; MTS = molar tooth sign; OFD = oral-facial-digital; SRPS = short-rib polydactyly syndrome

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From: Oral-Facial-Digital Syndrome Type I

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