Congenital Fibrosis of Extraocular Muscles (Ocular Motility Disorder) or Strabismus Syndromes Panel

Strabismus syndromes or congenital fibrosis of extraocular muscles (CFEOM) is an eye movement disorder characterized mainly by non-progressive, restrictive ophthalmoplegia [inability to move the eyes with or without ptosis (droopy eyelids)] of the extraocular muscles (EOM) and congenital blepharoptosis (Heidary et al. 2008).

Congenital fibrosis of extraocular muscles (CFEOM) is a heterogeneous group of strabismus syndromes that may be associated with other anomalies. Depending on the gene, the disease has been categorized into different types (Oystreck et al. 2011; Traboulsi 2004; Whitman et al. 1993).

CFEOM1A and CFEOM3B - due to KIF21A variants (missense and small deletion) (Human Gene Mutation Database).

CFEOM1B - due to TUBB3 variants (missense)

CFEOM2 - due to PHOX2A variants (missense, nonsense and splicing)

CFEOM3A - due to TUBB3 and TUBB2B variants (missense in both)

Duane-radial ray syndrome - due to SALL4 variants (missense, nonsense, small and large deletions and duplications)

Duane retraction syndrome DURS2 - due to CHN1 variants (missense)

Isolated Duane anomaly- due to HOXA1 variants (missense, nonsense, small deletions and duplications)

Horizontal gaze palsy with progressive scoliosis (HGPPS) - due to ROBO3 variants (missense, nonsense, splicing, small deletions and duplications)

Facial weakness, hearing loss, and complex or common strabismus - due to HOXB1 variants (missense)

Distal arthrogryposis associated with unilateral ptosis ophthalmoplegia, and/or strabismus ECEL1 variants (missense, nonsense, splicing, small deletions and duplications)

CFEOM4, CFEOM5, Tukel syndrome (no genes identified yet)

CFEOM1A, CFEOM1B, CFEOM3, CFEOM3 with polymicrogyria are inherited in an autosomal dominant (AD) manner. CFEOM2 is inherited in an autosomal recessive manner. Other syndromic disorders CHN1and SALL4-associated Duane syndromes are inherited in an AD manner. Isolated DA, HGPPS, HOXB1 and ECEL1-associated disorders are inherited in an AR manner (Whitman et al. 1993)

See individual gene test descriptions for information on molecular biology of gene products.

This panel typically provides ≥98% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Predicting clinical sensitivity for this panel is challenging due to genetic heterogeneity of Congenital fibrosis of extraocular muscles (CFEOM). Approximately 55% of the CFEOM cases are due to pathogenic variants in KIF21A , ~35% cases are due to TUBB3, ~10% cases are due to PHOX2A and <1% of the cases are due to TUBB2B (Whitman et al. 1993).

To our knowledge, only SALL4 has been reported have recurrent copy number variants. No other genes in this panel are reported to have any copy number variants to date (Human Gene Mutation Database).