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Cone-Rod Dystrophy via the CNNM4 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
4127 CNNM4 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4127CNNM481479 81479(x2) $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

Cone-rod dystrophy (CORD/CRD) is a rare hereditary retinal disorder with a worldwide prevalence of ~1 in 40,000. CRD is characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia and epiphora in bright light, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel 2007). Jalili syndrome, which is an autosomal recessive cone-rod dystrophy and amelogenesis imperfecta, is characterized by a combination of photophobia and dental anomalies (Jalili 2010; Parry et al. 2009; Polok et al. 2009).

Genetics

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and, rarely, X-linked (xl) inheritance (Hamel 2007). So far, about 25 genes have been implicated in different forms of CRD (RetNet). One of the ACDP (ancient conserved domain protein) family members CNNM4 (also known as ACDP4) is involved with arCRD. Quantitative PCR studies of the 4 members of ACDP (CNNM1-4) revealed that the CNNM4 is highly expressed in the retina, whereas CNNM1-3 showed markedly higher expression in brain than retina (Parry et al. 2009). CNNM4 and CNNM2 share high amino acid sequence identity (81.4%) and both are implicated in magnesium transport and biomineralization. CNNM4 is predominantly localized in the ganglion cell layers, the inner and outer plexiform layers, and the inner and outer photoreceptor segments of the retina (Parry et al. 2009, de Baaij et al. 2012). Immunostaining of CNNM4 indicates that it is also localized on soma and dendrites of neurons (Guo et al. 2005). These results suggest a possible role of CNNM4 in the maintenance of the ionic content of the extracellular space around the axons, dendrites, synapses in the neural retina and also in tooth enamel formation and in ameloblasts of the developing teeth (Luder et al. 2013; Parry et al. 2009; Guo et al. 2005). CNNM4 is shown to interact with cytochrome oxydase 11 (COX11) to regulate metal ion homeostasis and transport (Guo et al. 2005). Mutations in CNNM4 have been reported to cause CRD and Jalili syndrome due to abnormal ion homeostasis (Polok et al. 2009; Gómez García et al. 2011; Human Gene Mutation Database). Over ten pathogenic variations in CNNM4 have been reported.

Clinical Sensitivity - Sequencing with CNV PGxome

A CNNM4 mutation analysis in seven ethnically diverse families detected mutations in all Jalili syndrome affected members, and each mutation cosegregated consistently with the disease phenotype. These mutations were not present in 96 control chromosomes (Parry et al. 2009).

A CNNM4 mutational screening in seven ethnically diverse families affected by autosomal recessive cone-rod dystrophy and amelogenesis imperfecta identified gross deletions in two families (Parry et al. 2009).

Testing Strategy

This test provides full coverage of all coding exons of the CNNM4 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

All patients with symptoms suggestive of Cone-rod dystrophy. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CNNM4.

Gene

Official Gene Symbol OMIM ID
CNNM4 607805
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Jalili Syndrome AR 217080

Related Test

Name
Amelogenesis Imperfecta Panel

Citations

  • de Baaij JHF, Stuiver M, Meij IC, Lainez S, Kopplin K, Venselaar H, Muller D, Bindels RJM, Hoenderop JGJ. 2012. Membrane Topology and Intracellular Processing of Cyclin M2 (CNNM2). J Biol Chem 287: 13644–13655. PubMed ID: 22399287
  • Gómez García I, Oyenarte I, Martínez-Cruz LA. 2011. Purification, crystallization and preliminary crystallographic analysis of the CBS pair of the human metal transporter CNNM4. Acta Crystallographica Section F Structural Biology and Crystallization Communications 67: 349–353. PubMed ID: 21393841
  • Guo D, Ling J, Wang M-H, She J-X, Gu J, Wang C-Y. 2005. Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis. Mol. Pain 1: 15. PubMed ID: 15840172
  • Hamel CP. 2007. Cone rod dystrophies. Orphanet J Rare Dis 1;2:7. PubMed ID: 17270046
  • Human Gene Mutation Database (Bio-base).
  • Jalili IK. 2010. Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs. Eye 24: 1659–1668. PubMed ID: 20706282
  • Luder HU, Gerth-Kahlert C, Ostertag-Benzinger S, Schorderet DF. 2013. Dental Phenotype in Jalili Syndrome Due to a c.1312 dupC Homozygous Mutation in the CNNM4 Gene. PLoS ONE 8: e78529. PubMed ID: 24194943
  • Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, et al. 2009. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta. Am J Hum Genet 84: 266–273. PubMed ID: 19200525
  • Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, et al. 2009. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta. The American Journal of Human Genetics 84: 266–273.
  • Polok B, Escher P, Ambresin A, Chouery E, Bolay S, Meunier I, Nan F, Hamel C, Munier FL, Thilo B, Mégarbané A, Schorderet DF. 2009. Mutations in CNNM4 Cause Recessive Cone-Rod Dystrophy with Amelogenesis Imperfecta. The American Journal of Human Genetics 84: 259–265. PubMed ID: 19200527
  • RetNet: Genes and Mapped Loci Causing Retinal Diseases

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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