Oculofaciocardiodental Syndrome and Lenz Microphthalmia Syndrome via the BCOR Gene

Oculofaciocardiodental syndrome or OFCD is a multisystemic disorder. Females affected with OFCD commonly have congenital cataracts and microphthalmia, long narrow face with a short pointed nose, broad nasal tip, long philtrum and palatal abnormalities. Dental abnormalities include persistent primary teeth, oligodontia, and canine radiculomegaly. Skeletal abnormalities include syndactyly and hammer toes. Congenital cardiac defects, most commonly atrial and ventricular septal defects, are also associated with OFCD (Gorlin et al. Am J Med Genet 63:290-292, 1996; Hilton et al. Eur J Hum Genet 17:1325-1335, 2009). Male patients with X-linked Lenz microphthalmia syndrome present with unilateral or bilateral microphthamia, anophthalmia, simple ears, hearing defects, atrial septal defects and mild to severe mental retardation. Digital defects including duplicated thumbs, syndactyly, clinodactyly, and camptodactyly are also common features of Lenz microphthamia syndrome (Ng, D. GeneReviews).

OFCD and Lenz microphthalmia syndrome are allelic disorders caused by mutations in the BCOR gene (BCL6-corepressor). BCOR is a transcriptional repressor that physically interacts with a polycomb group complex, which has H2A monoubiquitination activity, and a SCF box, which has H3K36 demethylase activity to repress transcription of BCL6 target genes (Gearhart et al. Mol Cell Biol 26:6680-6689, 2006). OFCD is inherited in an X-linked dominant manner with presumed male lethality caused by loss of function mutations in BCOR. All documented causative mutations in female patients with OFCD are chain terminating mutations in BCOR (nonsense, splicing, frameshifts and large deletions) located throughout the coding region. The clinical phenotype of females with OFCD may be variable due to X-inactivation and somatic mocaicism (Hilton et al. Eur J Hum Genet 17:1325-1335, 2009). Missense mutation (c.254 C>T, p.Pro85Leu) in BCOR has been found in two unrelated males with X-linked recessive Lenz microphthalmia syndrome (Ng et al. Nat Genet 36:411–416, 2004; Hilton et al. Eur J Hum Genet 17:1325-1335, 2009).

The great majority of patients (61/64) diagnosed with OFCD have been found to have truncating mutations in BCOR (Ng et al. Nat Genet 36:411–416, 2004; Horn et al. Eur J Hum Genet 13:563–569, 2005; Hilton et al. Eur J Hum Genet 17:1325-1335, 2009). The clinical sensitivity for Lenz microphthamia syndrome is presumed to be low; one study found causative mutations in BCOR in one out of 21 patients (Hilton et al. Eur J Hum Genet 17:1325-1335, 2009).

This test provides full coverage of all coding exons of the BCOR 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).

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).