OFD1-Related Disorders via the OFD1 Gene

Oral-Facial-Digital syndrome type 1 (OFD1) is a developmental disorder with variable expressivity characterized by oral anomalies (lobed tongue, cleft palate, gingival frenulae, dental abnormalities); facial anomalies (ocular hypertelorism, hypoplasia of the alae nasi, upper lip median cleft, micrognathia); digital anomalies (brachydactyly, syndactyly, clinodactyly; preaxial or postaxial polydactyly, duplicated hallux); brain anomalies (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation) and polycystic kidneys. In addition, about 50% of patients diagnosed with OFD1 have learning disabilities (Gorlin and Psaume 1962; Feather et al. 1997; Ferrante et al. 2001).

Joubert Syndrome (JBTS) is marked by mid-hindbrain malformation, retinal dystrophy, cystic renal disease, hepatic fibrosis and polydactyly (Doherty 2009). Mid-hindbrain malformation, which can be readily identified as a “Molar Tooth Sign” (MTS) using Magnetic Resonance Imaging (MRI), typically leads to hypotonia, ataxia, abnormal eye movements and intellectual disability. MTS is pathognomonic for JBTS.

Retinitis Pigmentosa is an inherited degenerative disease of the retina characterized by abnormalities of the photoreceptors or the retinal pigment epithelium. It is a progressive disease. Symptoms usually begin with night blindness, progressing to constriction of the peripheral visual field and, eventually, to loss of central vision. The age of onset varies from childhood to middle age (Gu et al. 1999).

OFD1 is embryonic male-lethal X-linked dominant condition caused by pathogenic variants in the OFD1 gene (Feather et al. 1997; Ferrante et al. 2001). OFD1 encodes oral-facial-digital syndrome 1 protein (OFD1), which is localized to centrosomes and basal bodies of ciliated cells suggesting a role in cilia motility and function (Ferrante et al. 2009; Coene et al. 2009). A mix of missense, nonsense, frameshift and splicing variants as well as gross deletions have been reported in OFD1 (Ferrante et al. 2001; Rakkolainen et al. 2002; Morisawa et al. 2004; Budny et al. 2006; Coene et al. 2009). Roughly 75% of OFD1 cases are simplex (Toriello and Franco 2013). Severity of the phenotype correlates with the reduction in protein length (Thauvin-Robinet et al. 2006). Coene et al. predicted that all pathogenic variants before residue 631 are lethal for males and cause OFD I syndrome in females, while males with JBS10 who may live beyond the age of 30 years have pathogenic variants located in the coiled-coil domain nearest to the C terminus (Coene et al. 2009).

Roughly 80% of females with OFD1 syndrome are found to have OFD1 pathogenic variant detected by sequencing (Prattichizzo et al. 2008). Approximately 5% of females with OFD1 syndrome will have a gross deletion (Thauvin-Robinet et al 2009). The clinical sensitivity for Joubert syndrome, Simpson-Golabi-Behmel syndrome, and retinitis pigmentosa is unknown due to the paucity of documented cases. Analytical sensitivity should be high for Joubert syndrome, Simpson-Golabi-Behmel syndrome, and retinitis pigmentosa since all OFD1 pathogenic variants reported to date are expected to be detected by sequencing.

Roughly 20% of individuals with OFD1 syndrome who have a negative finding by sequencing have been found to have a gross deletion in OFD1 (Thauvin-Robinet et al. 2009).

This test provides full coverage of all coding exons of the OFD1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

We also sequence the intronic c.935+706A>G variant (Webb et al. 2012).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).