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

Congenital fibrosis of extraocular muscles (CFEOM) or strabismus syndromes are eye movement disorders 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. PubMed ID: 18214786). The estimated prevalence of CFEOM is 1:230,000 (Reck et al. 1998. PubMed ID: 9797671). Duane syndrome accounts for 1-5% of all cases of CFEOM (Barry et al. 2019. PubMed ID: 20301369).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

Congenital fibrosis of extraocular muscles (CFEOM) is a heterogeneous group of strabismus syndromes that may be associated with other anomalies. Depending on the affected gene, the disease has been categorized into different types (Oystreck et al. 2011. PubMed ID: 21317732; Traboulsi. 2004. PubMed ID: 15747768; Whitman et al. 1993. PubMed ID: 20301522). Pathogenic variants in genes involved in the embryological development of cranial neuromuscular units, in particular transcription factors associated with hindbrain differentiation, neural crest identity, axon guidance, and axon construction are associated with CFEOMs (Vivian. 2020. PubMed ID: 31804624).

Missense variants and small deletions in KIF21A cause CFEOM1A and CFEOM3B, while TUBB3 missense variants are causative for CFEOM1B and CFEOM3A. De novo pathogenic variants are commonly reported in TUBB3 associated with CFEOM3 (Tischfield et al. 2010. PubMed ID: 20074521). Missense variants in TUBB2B also cause CFEOM3A. CFEOM2 is due to pathogenic variants in PHOX2A, including missense, nonsense and splicing variants. Missense and nonsense variants in COL25A1 cause cranial dysinnervation disorder (CFEOM5). No genes have yet been identified for Tukel syndrome/CFEOM4 (Human Gene Mutation Database).

Pathogenic variants in SALL4 cause Duane-radial ray syndrome. The spectrum of causative variants includes missense and nonsense variants as well as small and large deletions and duplications. Duane retraction syndrome is due to missense variants in CHN1 and dominant negative loss of function variants, such as small and large deletions, in MAFB. Variants in HOXA1 (missense and nonsense variants and small deletions and duplications) are causative for isolated Duane anomaly (DA; Human Gene Mutation Database).

Horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by pathogenic variants ROBO3, including missense, nonsense, and splicing variants as well as small deletions and duplications. Missense variants in HOXB1 cause facial weakness, hearing loss, and complex or common strabismus. Distal arthrogryposis associated with unilateral ptosis ophthalmoplegia, and/or strabismus is due to ECEL1 variants (missense, nonsense, and splicing variants; small deletions and duplications). Missense variants in PLXND1 and REV3L cause Moebius syndrome (MBS). De novo pathogenic variants in PLXND1 and REV3L have been documented causative for MBS (Tomas-Roca et al. 2015. PubMed ID: 26068067; Human Gene Mutation Database).

CFEOM1A, CFEOM1B, CFEOM3, and CFEOM3 with polymicrogyria are inherited in an autosomal dominant (AD) manner. CFEOM2 is inherited in an autosomal recessive (AR) manner. CHN1 and SALL4-associated Duane syndromes are inherited in an AD manner. Isolated DA, HGPPS, HOXB1, ECEL1, and COL25A1-associated disorders are inherited in an AR manner (Whitman et al. 1993. PubMed ID: 20301522; Barry et al. 2019. PubMed ID: 20301369).

The c.2860C>T (p.Arg954Trp) variant in KIF21A (not documented in gnomAD) is the most common variant reported in individuals with autosomal dominant congenital fibrosis of extraocular muscles (Yamada et al. 2003. PubMed ID: 14595441; Rudolph et al. 2009. PubMed ID: 19551685; Yang et al. 2010. PubMed ID: 21042561). 

Haploinsufficient and dominant-negative variants in MAFB result in major abnormalities of hindbrain and cranial nerve development. Studies in Mafb-knockout mice showed that the primary cause of Duane retraction syndrome is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development (Park et al. 2016. PubMed ID: 27181683). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Predicting clinical sensitivity for this panel is challenging due to genetic heterogeneity of congenital fibrosis of extraocular muscles (CFEOM). Approximately 55% of CFEOM cases are due to pathogenic variants in KIF21A , ~35% of cases are due to pathogenic variants in TUBB3, ~10% of cases are due to pathogenic variants in PHOX2A, and <1% of cases are due to pathogenic variants in TUBB2B (Whitman et al. 1993. PubMed ID: 20301522).

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

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.5% 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. 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).