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

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
2685 CHN1 81479,81479 Order Options and Pricing
COL25A1 81479,81479
ECEL1 81479,81479
HOXA1 81479,81479
HOXB1 81479,81479
KIF21A 81479,81479
MAFB 81479,81479
PHOX2A 81479,81479
PLXND1 81479,81479
REV3L 81479,81479
ROBO3 81479,81479
SALL4 81479,81479
TUBB2B 81479,81479
TUBB3 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
2685Genes x (14)81479 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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.

Genetics

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, HOXB1ECEL1, 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.

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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.

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

Indications for Test

Patients with congenital abnormalities of eye movements are candidates (Oystreck et al. 2011. PubMed ID: 21317732).

Genes

Official Gene Symbol OMIM ID
CHN1 118423
COL25A1 610004
ECEL1 605896
HOXA1 142955
HOXB1 142968
KIF21A 608283
MAFB 608968
PHOX2A 602753
PLXND1 604282
REV3L 602776
ROBO3 608630
SALL4 607343
TUBB2B 612850
TUBB3 602661
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Barry et al. 2019. PubMed ID: 20301369
  • Heidary et al. 2008. PubMed ID: 18214786
  • Human Gene Mutation Database (Bio-base).
  • Oystreck et al. 2011. PubMed ID: 21317732
  • Park et al. 2016. PubMed ID: 27181683
  • Reck et al. 1998. PubMed ID: 9797671
  • Rudolph et al. 2009. PubMed ID: 19551685
  • Tischfield et al. 2010. PubMed ID: 20074521
  • Tomas-Roca et al. 2015. PubMed ID: 26068067
  • Traboulsi. 2004. PubMed ID: 15747768
  • Vivian. 2020. PubMed ID: 31804624
  • Whitman et al. 1993. PubMed ID: 20301522
  • Yamada et al. 2003. PubMed ID: 14595441
  • Yang et al. 2010. PubMed ID: 21042561

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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