Orofaciodigital Syndrome V

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.

Clinical Features

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 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.

Inheritance

Munke et al. (1990) considered the mode of inheritance to be autosomal recessive.

Mapping

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.

Molecular Genetics

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 neither was 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.