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FRMD7-Associated X-linked Congenital Nystagmus 1 (NYS1) via the FRMD7 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1639 FRMD7$940.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

A FRMD7 mutational screening in 14 families with two or more affected individuals of either sex identified mutations in 8 families (57%)(Tarpey et al. 2006). Also in the same study, in a cohort of 42 simplex cases (who had undergone careful clinical and electrophysiological investigation to exclude other causes of inherited CN, 3 patients (7%) were found to have FRMD7 mutations. All identified mutations were absent in 300 male control chromosomes. Another study showed that FRMD7 mutations account for approximately 47% of X-linked nystagmus in Chinese patients (Du et al. 2011). Analytical sensitivity is expected to be high because approximately 90% of the FRMD7 causative mutations are detectable by this method (Thomas et al. 1993). Only one large intragenic deletion in FRMD7 has been reported so far (Fingert et al. 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FRMD7$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Congenital nystagmus (CN) is a relatively common neurological-ocular disorder with an estimated prevalence of approximately 1/1000 live births. However, it can also occur early in the child’s vision development. CN is clinically characterized by bilateral involuntary rhythmic horizontal (predominant) and conjugate ocular oscillations that may result in significantly reduced visual acuity (Cabot et al. 1999; Tarpey et al. 2006; Sarvananthan et al. 2009; Zhu et al. 2013; Zhang et al. 2014).

Genetics

CN is a genetically heterogeneous disorder that is reported to exhibit X-linked, autosomal dominant and autosomal recessive modes of inheritance. To date, five chromosomal loci (NYS 1–5) have been mapped that are linked to CN pathogenesis (Thomas et al. 2011). FRMD7-associated CN is inherited in an X-linked mode with incomplete penetrance in female carriers (~50%) (Tarpey et al. 2006). FRMD7, which is located on Xq26-q27 encodes FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain-containing 7 protein, a member of FERM protein family. It has been reported that FRMD7 expression is spatiotemporally regulated in the brain during embryonic and fetal development, particularly in regions of the brain associated with oculomotor control. These results suggest that FRMD7 has a specific role in the control of eye movement and gaze stability (Betts-Henderson et al. 2010; Tarpey et al. 2006). Recently, Watkins et al. (2013) reports that FRMD7 mutations disrupt the FRMD7 interaction with CASK, a MAGUK (Membrane-associated guanylate kinases) family member, which further prevents their co-localization at the plasma membrane and impairs CASK-induced neurite outgrowth during development of the oculomotor neural network and results in nystagmus (Watkins et al. 2013). So far, about 50 pathogenic sequence variations (missense/nonsense, splicing, small insertions, small and gross deletions) in FRMD7 that are associated with X-linked Congenital Nystagmus 1 have been reported (Human Gene Mutation Database).

Testing Strategy

This test involves bidirectional DNA Sanger sequencing of all coding exons (1-12) of the FRMD7 gene, plus ~20 bp of flanking non-coding DNA on either side of each exon are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

All patients with symptoms suggestive of nystagmus, even the simplex cases (please see the clinical sensitivity section).

Gene

Official Gene Symbol OMIM ID
FRMD7 300628
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
X-Linked Infantile Nystagmus 310700

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Betts-Henderson J, Bartesaghi S, Crosier M, Lindsay S, Chen H-L, Salomoni P, Gottlob I, Nicotera P. 2010. The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development. Human Molecular Genetics 19: 342–351. PubMed ID: 19892780
  • Cabot A, Rozet J-M, Gerber S, Perrault I, Ducroq D, Smahi A, Souied E, Munnich A, Kaplan J. 1999. A gene for X-linked idiopathic congenital nystagmus (NYS1) maps to chromosome Xp11. 4-p11. 3. The American Journal of Human Genetics 64: 1141–1146. PubMed ID: 10090899
  • Du W, Bu J, Dong J, Jia Y, Li J, Liang C, Si S, Wang L. 2011. A novel frame-shift mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a Chinese family. Molecular vision 17: 2765. PubMed ID: 22065930
  • Fingert JH, Roos B, Eyestone ME, Pham JD, Mellot ML, Stone E. 2010. Novel intragenic FRMD7 deletion in a pedigree with congenital X-linked nystagmus. Ophthalmic Genet. 31: 77–80. PubMed ID: 20450309
  • Human Gene Mutation Database (Bio-base).
  • Sarvananthan N, Surendran M, Roberts EO, Jain S, Thomas S, Shah N, Proudlock FA, Thompson JR, McLean RJ, Degg C, Woodruff G, Gottlob I. 2009. The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey. Investigative Ophthalmology & Visual Science 50: 5201–5206. PubMed ID: 19458336
  • Tarpey P, Thomas S, Sarvananthan N, Mallya U, Lisgo S, Talbot CJ, Roberts EO, Awan M, Surendran M, McLean RJ, Reinecke RD, Langmann A, et al. 2006. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nature Genetics 38: 1242–1244. PubMed ID: 17013395
  • Thomas MG, Crosier M, Lindsay S, Kumar A, Thomas S, Araki M, Talbot CJ, McLean RJ, Surendran M, Taylor K, Leroy BP, Moore AT, et al. 2011. The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. Brain 134: 892–902. PubMed ID: 21303855
  • Thomas MG, Thomas S, Kumar A, Proudlock FA, Gottlob I. 1993. FRMD7-Related Infantile Nystagmus. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301748
  • Watkins RJ, Patil R, Goult BT, Thomas MG, Gottlob I, Shackleton S. 2013. A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Human Molecular Genetics 22: 2105–2118. PubMed ID: 23406872
  • Zhang X, Ge X, Yu Y, Zhang Y, Wu Y, Luan Y, Sun J, Qu J, Jin Z-B, Gu F. 2014. Identification of Three Novel Mutations in the FRMD7 Gene for X-linked Idiopathic Congenital Nystagmus. Scientific Reports 4: PubMed ID: 24434814
  • Zhu Y, Zhuang J, Ge X, Zhang X, Wang Z, Sun J, Yang J, Gu F. 2013. Identifcation of a Novel Mutation p.I240T in the FRMD7 gene in a Family with Congenital Nystagmus. Scientific Reports 3: PubMed ID: 24169426
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TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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