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OculoDentoDigital Dysplasia (ODDD) via the GJA1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9251 GJA1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9251GJA181479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

OculoDentoDigital Dysplasia (ODDD) is a autosomal dominant (AD) disorder. Rarely, autosomal recessive (AR) transmission also been reported. ODDD is characterized by pleiotropic malformations of the eyes, face, limbs, and dentition. High penetrance and marked intra- and inter-familial phenotypic variability has been reported in ODDD (Paznekas et al. 2009). Glaucoma is the main cause of vision loss in ODDD. Other ocular malformations include microphthalmia, microcornea, fine porous spongy iris abnormalities, and cataracts (Musa et al. 2008). Characteristic facial appearance includes a long narrow nose, hypoplastic alae nasi, anteverted nostrils, and a prominent columella and nasal bridge. Dental abnormalities include microdontia, hypodontia, and enamel hypoplasia. Digital abnormalities include syndactyly of finger 4/5, and hypoplastic phalanges (Frasson et al. 2004; Musa et al. 2008; Jamsheer et al. 2014). Less common symptoms include hypotrichosis, intracranial calcifications, and conductive deafness secondary to recurrent otitis media (Frasson et al. 2004).

Genetics

ODDD is caused by mutations in the GJA1 (gap junction alpha 1) gene, which is located on chromosome 6q21–q23.2. ODDD is mainly an AD disorder due to mutations in GJA1. However, rarely AR inheritance has also been reported. The AD mutations in GJA1 have been reported to reduce channel function and act in dominant-negative manner (Richardson 2005). The two AR mutations that have been reported so far are p.R33* and p.Arg76His. The homozygous carriers of the p.R33*mutation had severe developmental defects typically associated with ODDD. When the p.Arg76 residue is substituted by serine (p.Arg76Ser), the patients showed the ODDD phenotype with dominant inheritance. A different substitution of the same amino acid (p.Arg76His) exhibited recessive inheritance with a Hallermann-Streiff syndrome (HSS)/ODDD overlapping phenotype. HSS is characterized by typical skull shape, hypotrichosis, congenital cataracts, beaked nose and dental anomalies (Pizzuti et al. 2004; Richardson et al. 2004). Functional studies have shown that the p.Arg76His mutant exhibited no dominant-negative properties and p.R33* showed modest dominant negative effect (Huang et al. 2013). To date, about 100 causative mutations involved with ODDD have been reported in GJA1. The great majority of these are missense mutations (97%) (Jamsheer et al. 2014; Human Gene Mutation Database).

GJA1 encoded protein connexin 43 (Cx43) is expressed in the most anterior portion of the forebrain and in the developing neural folds. Additionally, it is expressed in the developing and adult eye and also during early limb development (Richardson et al. 2004). Mouse model studies indicated that Cx43 is a major component of the gap junctions between pigmented and non-pigmented cells of the double layered epithelium of the ciliary body and is required for the production of the aqueous humor that is in turn required for the generation of normal intraocular pressure and nourishment of the postnatal lens (Calera et al. 2006).

Clinical Sensitivity - Sequencing with CNV PGxome

A GJA1 mutation analysis study detected GJA1 mutations in all ODDD affected patients (177 affected individuals from 54 families) (Paznekas et al. 2003; Paznekas et al. 2009).

No gross deletions or duplications have been reported in the GJA1 gene (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the GJA1 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).

Indications for Test

Candidates for this test are patients with symptoms consistent with Oculodentodigital dysplasia (ODDD), and family members of patients with known mutations. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GJA1.

Gene

Official Gene Symbol OMIM ID
GJA1 121014
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Calera MR, Topley HL, Liao Y, Duling BR, Paul DL, Goodenough DA. 2006. Connexin43 is required for production of the aqueous humor in the murine eye. Journal of Cell Science 119: 4510–4519. PubMed ID: 17046998
  • Frasson M, Calixto N, Cronemberger S, Aguiar RALP de, Leão LL, Aguiar MJB de. 2004. Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance. Ophthalmic Genet. 25: 227–236. PubMed ID: 15512999
  • Huang T, Shao Q, MacDonald A, Xin L, Lorentz R, Bai D, Laird DW. 2013. Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. Journal of Cell Science 126: 2857-2866. PubMed ID: 23606748
  • Human Gene Mutation Database (Bio-base).
  • Jamsheer A, Sowinska-Seidler A, Socha M, Stembalska A, Kiraly-Borri C, Latos-Bieleńska A. 2014. Three novel GJA1 missense substitutions resulting in oculo-dento-digital dysplasia (ODDD) - further extension of the mutational spectrum. Gene 539: 157–161. PubMed ID: 24508941
  • Musa FU, Ratajczak P, Sahu J, Pentlicky S, Fryer A, Richard G, Willoughby CE. 2008. Ocular manifestations in oculodentodigital dysplasia resulting from a heterozygous missense mutation (L113P) in GJA1 (connexin 43). Eye 23: 549–555. PubMed ID: 18425059
  • Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, others. 2003. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. The American Journal of Human Genetics 72: 408–418. PubMed ID: 12457340
  • Paznekas WA, Karczeski B, Vermeer S, Lowry RB, Delatycki M, Laurence F, Koivisto PA, Maldergem L Van, Boyadjiev SA, Bodurtha JN, Wang Jabs E. 2009. GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Human Mutation 30: 724–733. PubMed ID: 19338053
  • Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B. 2004. A homozygousGJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Human Mutation 23: 286-286. PubMed ID: 14974090
  • Richardson R, Donnai D, Meire F, Dixon MJ. 2004. Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly. Journal of medical genetics 41: 60–67. PubMed ID: 14729836
  • Richardson RJ. 2005. A nonsense mutation in the first transmembrane domain of connexin 43 underlies autosomal recessive oculodentodigital syndrome. Journal of Medical Genetics 43: e37-e37. PubMed ID: 16816024

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


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.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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