Congenital Fibrosis of Extraocular Muscles (Ocular Motility Disorder) Type 3A via the TUBB3 Gene

Congenital fibrosis of extraocular muscles (CFEOM) is an eye movement disorder characterized mainly by non-progressive, restrictive ophthalmoplegia of the extraocular muscles (EOM) and congenital blepharoptosis (Heidary et al. 2008). Congenital fibrosis of extraocular muscles (CFEOM) is a heterogeneous disorder. Depending on the gene, the disease has been categorized into different types. CFEOM1 (due to KIF21A variants), CFEOM2 (due to ARIX variants), CFEOM3A (due to TUBB3 variants), CFEOM3B (due to KIF21A variants), and CFEOM4, CFEOM5 (no genes identified yet) (Oystreck et al. 2011; Traboulsi 2004).

CFEOM3A affected patients may have additional neurological signs or symptoms such as intellectual disability, social disability, facial weakness, and progressive sensorimotor axonal polyneuropathy (Andrews et al. 1993).

CFEOM3A is an autosomal dominant disorder, which is due to heterozygous variants in TUBB3. TUBB3 encodes neuron-specific beta-tubulin subunit, which is required for axon guidance and maintenance in mammals (Poirier et al. 2010; Tischfield et al. 2010). In vitro studies using yeast have shown that the TUBB3 causative variants can impair tubulin heterodimer formation and disrupt the interaction of microtubules with kinesin motors. This in turn leads to innervation abnormalities in the EOM during the development of oculomotor and/or trochlear nerves (Tischfield et al. 2010). CFEOM3A is variable, asymmetrical, and variably penetrant (~90%) (Doherty et al 1999). A mutation screen involving 29 unrelated families revealed that 13 had eight TUBB3 pathogenic variants and all occurred de novo (Tischfield et al. 2010). Severe phenotype has been reported in patients with de novo mutations in TUBB3 (Poirier et al. 2010). So far only missense variants have shown to be causative for TUBB3-associated disorders (Human Gene Mutation Database).

Predicting clinical sensitivity for the TUBB3 gene is challenging due to genetic heterogeneity of Congenital fibrosis of extraocular muscles. However, analytical sensitivity should be high as all the reported variants are detectable by sequencing. TUBB3 mutation screening in 6 unrelated individuals with sporadic CFEOM3A identified de novo pathogenic variants in all the affected patients (Tischfield et al. 2010).

This test provides full coverage of all coding exons of the TUBB3 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).