Alternative titles; symbols
SNOMEDCT: 722105002; ORPHA: 2919; DO: 0060375;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
1q32.1 | Orofaciodigital syndrome V | 174300 | Autosomal recessive | 3 | DDX59 | 615464 |
A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome-5 (OFD5) is caused by homozygous mutation in the DDX59 gene (615464) on chromosome 1q32.
Orofaciodigital syndrome V (OFD5) is an autosomal recessive disorder characterized by cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (summary by Faily et al., 2017).
Rischbieth (1910) pictured a Hindu patient with postaxial polydactyly and median cleft of the upper lip. His brother was identically affected. Thurston (1909) had earlier reported these brothers. The brothers had median cleft of the vermilion of the upper lip and postaxial polydactyly of the hands and feet. Rischbieth (1910) cited the family of Roux (1847) in which the father had unilateral harelip and 6 digits on all 4 limbs, whereas the son had double harelip and the same deformity of hands and feet. Khoo and Saad (1980) described the case of a 26-year-old male nurse of Indian descent. The proband for Thurston (1909) was a 20-year-old recruit for the Bengal police. Yet another case in an Indian male was reported by Gopalakrishna and Thatte (1982).
Munke et al. (1990) noted oral frenula as a finding in Thurston syndrome.
Shamseldin et al. (2013) studied 2 consanguineous multiplex Arab families with orofaciodigital syndrome. All affected individuals exhibited the core features of cleft palate, lobulated tongue, and polydactyly; all also had frontal bossing and intellectual disability. In published photographs, the polydactyly was postaxial, and a subtle midline lip defect was illustrated. In 1 family, 2 affected individuals also had cardiac anomalies, including tetralogy of Fallot (TOF) and ventricular septal defect; additional anomalies in the patient with TOF included scoliosis, fused kidneys, and agenesis of the corpus callosum. One of the 4 affected individuals in the other family also exhibited Hirschsprung disease.
Faily et al. (2017) described 3 patients, including 2 sibs, with OFD5 from apparently unrelated, consanguineous Pakistani families. All 3 patients had tongue hamartomas, low-set ears, profound microcephaly, developmental delay, and feeding difficulties. One sib (patient IV-5), an 8-year-old girl, also had a bifid tongue, downslanting palpebral fissures, hypotonia, ataxia, auditory loss, and joint laxity. Her 7-year-old brother (patient IV-6) also had a bifid tongue, high-arched palate, hypodontia, asymmetric dilation of the lateral ventricles on brain MRI, bilateral postaxial polydactyly, and an undescended testicle. Additional features in the unrelated patient (patient III-6), an 8-year-old girl, included cleft palate, ankyloglossia, absent lower central incisors, facial asymmetry, abnormal mandible, hypotonia, and cerebellar vermis hypoplasia. She also had a ventricular septal defect and eye abnormalities including unilateral ptosis and a unilateral dysplastic optic disc with a colobomatous appearance.
Salpietro et al. (2018) described 2 sibs with OFD5 and mutation in the DDX59 gene who were originally described by Salpietro et al. (2005) as having Oliver syndrome (258200). Both sibs had postaxial polydactyly, impaired intellectual development, and epilepsy. The older sib had a history of intrauterine growth retardation. He had bilateral postaxial polydactyly, bilateral 5th finger clinodactyly, and cutaneous syndactyly of fingers 2-5. He developed seizures in infancy, and subsequently had developmental delay and cognitive difficulties. Facial features included thick eyebrows, malocclusion, and high-arched palate. Brain MRI at 17 years of age demonstrated thinning of the cerebral cortex in front of the ventricular collateral trigone. Brain MRI at 30 years of age showed diffuse white matter signal abnormalities and multifocal cortical-subcortical infarcts involving both cerebral hemispheres. The younger sib developed generalized seizures at 4 months of age. She had postaxial polydactyly of the left hand, bilateral 5th finger clinodactyly, and cutaneous syndactyly of fingers 2-5. She also had postaxial polydactyly of the right foot with brachydactyly of toes 3-5. Other features included malocclusion, high-arched palate, and scoliosis. She had psychomotor delay, and a brain MRI at 13 years of age showed thinning of the cerebral cortex in front of the ventricular collateral trigone. Brain MRI at 21 years of age showed signal abnormalities in the subcortical and deep white matter of both cerebral hemispheres.
Munke et al. (1990) considered the mode of inheritance of OFD5 to be autosomal recessive. The transmission pattern of OFD5 in the families reported by Shamseldin et al. (2013) was consistent with autosomal recessive inheritance.
In 2 consanguineous multiplex Arab families with orofaciodigital syndrome, Shamseldin et al. (2013) performed autozygosity mapping and identified a shared minimal interval at chromosome 1q32.1 (chr1:197,262,220-201,811,027). Linkage analysis yielded a single peak, on chromosome 1, with a lod score of 5.8.
In an affected individual from each of 2 consanguineous multiplex Arab families with orofaciodigital syndrome mapping to chromosome 1q32.1, Shamseldin et al. (2013) performed exome sequencing and identified homozygosity for different missense variants in the DDX59 gene (V367G, 615464.0001; G534R, 615464.0002). The mutations segregated with disease in each family and were not found in 300 ethnically matched exomes or 200 ethnically matched controls. Shamseldin et al. (2013) sequenced the DDX59 gene in 4 more simplex OFD patients but did not detect any pathogenic mutations.
In 2 Pakistani sibs (family 1) and an apparently unrelated Pakistani patient (family 2) with OFD5, all born to consanguineous parents, Faily et al. (2017) identified homozygosity for a mutation in the DDX59 gene (c.1859G-T; 615464.0003). The mutation was identified by a combination of autozygosity mapping, whole-exome sequencing, and Sanger sequencing. The molecular status of the parents was not reported. The mutation was not present in the dbSNP or EVS databases and was present in the ExAC database in only heterozygous state at an allele frequency of 0.00088%. Functional studies were not performed.
In 2 Italian sibs with OFD5, who were originally described by Salpietro et al. (2005) as having Oliver syndrome, Salpietro et al. (2018) identified a homozygous 1-bp deletion (615464.0004) in the DDX59 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Semiquantitative PCR from patient lymphoblastoid cells demonstrated reduction in the mutant cDNA compared to wildtype controls and absence of DDX59 protein expression. Increased SHH (600725) protein expression was also demonstrated in patient lymphoblastoid cells, indicating possible disturbance of the Hedgehog pathway.
Faily, S., Perveen, R., Urquhart, J., Chandler, K., Clayton-Smith, J. Confirmation that mutations in DDX59 cause an autosomal recessive form of oral-facial-digital syndrome: further delineation of the DDX59 phenotype in two new families. Europ. J. Med. Genet. 60: 527-532, 2017. [PubMed: 28711741] [Full Text: https://doi.org/10.1016/j.ejmg.2017.07.009]
Gopalakrishna, A., Thatte, R. L. Median cleft lip associated with bimanual hexadactyly and bilateral accessory toes: another case. Brit. J. Plast. Surg. 35: 354-355, 1982. [PubMed: 7150858] [Full Text: https://doi.org/10.1016/s0007-1226(82)90126-6]
Khoo, C. T. K., Saad, M. N. Median cleft of the upper lip in association with bilateral hexadactyly and accessory toes. Brit. J. Plast. Surg. 33: 407-409, 1980. [PubMed: 7426821] [Full Text: https://doi.org/10.1016/0007-1226(80)90103-4]
Munke, M., McDonald, D. M., Cronister, A., Stewart, J. M., Gorlin, R. J., Zackai, E. H. Oral-facial-digital syndrome type VI (Varadi syndrome): further clinical delineation. Am. J. Med. Genet. 35: 360-369, 1990. [PubMed: 2309783] [Full Text: https://doi.org/10.1002/ajmg.1320350310]
Rischbieth, H. Hare-lip and cleft palate.In: Treasury of Human Inheritance, Part IV. Vol. I. London: Cambridge Univ. Press (pub.) 1910. Note: Plate J.
Roux, (NI). Bec-de-lievre unilateral. Gaz. Hop. (2nd series) 9: 274 only, 1847.
Salpietro, C. D., Briuglia, S., Bertuccio, G., Rigoli, L., Mingarelli, R., Dallapiccola, B. Report of a third family with Oliver syndrome. (Letter) Am. J. Med. Genet. 139A: 159-161, 2005. [PubMed: 16278897] [Full Text: https://doi.org/10.1002/ajmg.a.30999]
Salpietro, V., Efthymiou, S., Manole, A., Maurya, B., Wiethoff, S., Ashokkumar B., Cutrupi, M. C., Dipasquale, V., Manti, S., botia, J. A., Ryten, M., Vandrovcova, J., Bello, O. D., Bettencourt, C., Mankad, K., Mukherjee, A., Mutsuddi, M., Houlden, H. A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function. Hum. Mutat. 39: 187-192, 2018. [PubMed: 29127725] [Full Text: https://doi.org/10.1002/humu.23368]
Shamseldin, H. E., Rajab, A., Alhashem, A., Shaheen, R., Al-Shidi, T., Alamro, R., Al Harassi, S., Alkuraya, F. S. Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome. Am. J. Hum. Genet. 93: 555-560, 2013. [PubMed: 23972372] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.012]
Thurston, E. O. A case of median hare-lip associated with other malformations. Lancet 174: 996-997, 1909. Note: Originally Volume II.