Forms

Hypochondroplasia via the FGFR3 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
428 FGFR3$560.00 81404 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
This test is predicted to detect disease mutations in >70% of affected individuals (Prinos et al. Hum Mol Genet 4:2097–2101, 1995; Prinster et al. Am J Med Genet 75:109–112, 1998; Ramaswami et al. J Pediatr 133:99–102, 1998; Grigelioniene et al. Hum Mut 11:333, 1998; Bellus et al. Am J Hum Genet 67:1411–1421, 2000; Thauvin-Robinet et al. Am J Med Genet A 119:81–84, 2003).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FGFR3$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
Hypochondroplasia (OMIM#146000) is a relatively common skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly (Francomano. GeneReviews 2005). The skeletal features are very similar to achondroplasia but usually tend to be milder. Children usually present as toddlers or school-age children with failure to grow. As the age of the children increases, limb disproportion and other features become more prominent.
Genetics
Hypochondroplasia is inherited in an autosomal dominant manner. The majority of new cases result from a de novo mutation. FGFR3 is the only gene known to be associated with hypochondroplasia; however, genetic heterogeneity is suspected. Two recurrent FGFR3 mutations (c.1620C>A and c.1620C>G) resulting in p.Asn540Lys in exon 13 that encodes the ATP-binding segment of the tyrosine kinase domain have been shown to be common cause of hypochondroplasia (Bellus et al. Nat Genet 10:357–359, 1995; Prinos et al. Hum Mol Genet 4:2097–2101, 1995). Sequence analysis of FGFR3 exons 7, 9, 10, 13, and 15 detects other rare FGFR3 mutations associated with hypochondroplasia. FGFR3 gene encodes fibroblast growth factor receptor-3, a member of the FGFR family. Like all of the FGFRs, FGFR3 is a membrane-spanning tyrosine kinase receptor with an extracellular ligand-binding domain consisting of three immunoglobulin subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain (Green et al. Bioessays 18:639–646. 1996).
Testing Strategy
This test involves bidirectional sequencing using genomic DNA of 5 selected coding exons (exon 7, 9, 10, 13, 15) of the FGFR3 gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Candidates for this test are patients with clinical features consistent with hypochondroplasia and family members of patients who have a known FGFR3 mutation.

Gene

Official Gene Symbol OMIM ID
FGFR3 134934
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Hypochondroplasia 146000

Related Tests

Name
FGFR3-Related Disorders via the FGFR3 Gene
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Craniosynostosis and Related Disorders Sequencing Panel
Craniosynostosis via the MSX2 Gene
Facial Dysostosis Related Disorders Sequencing Panel
Frontonasal Dysplasia (Frontorhiny) via the ALX3 Gene
Nonsyndromic Hearing Loss and Deafness Sequencing Panel
Thanatophoric Dysplasia (TD) via the FGFR3 Gene
Treacher Collins Syndrome/ Mandibulofacial Dysostosis/Miller syndrome/Acrofacial Dysostosis, Nagar Type Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA. 1995. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat. Genet. 10: 357–359. PubMed ID: 7670477
  • Bellus, G. A., et.al. (2000). "Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype." Am J Hum Genet 67(6): 1411-21. PubMed ID: 11055896
  • Francomano, Clair A MD, FACMG (2005). "Hypochondroplasia."
  • Green, P. J., et.al. (1996). "Promiscuity of fibroblast growth factor receptors." Bioessays 18(8): 639-46. PubMed ID: 8760337
  • Grigelioniene, G., et.al. (1998). "A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online." Hum Mutat 11(4): 333. PubMed ID: 10215410
  • Prinos P, Costa T, Sommer A, Kilpatrick MW, Tsipouras P. 1995. A common FGFR3 gene mutation in hypochondroplasia. Human molecular genetics 4: 2097–2101. PubMed ID: 8589686
  • Prinster, C., et.al. (1998). "Comparison of clinical-radiological and molecular findings in hypochondroplasia." Am J Med Genet 75(1): 109-12. PubMed ID: 9450868
  • Ramaswami, U., et.al. (1998). "Genotype and phenotype in hypochondroplasia." J Pediatr 133(1): 99-102. PubMed ID: 9672519
  • Thauvin-Robinet, C., et.al. (2003). "Hypochondroplasia and stature within normal limits: another family with an Asn540Ser mutation in the fibroblast growth factor receptor 3 gene." Am J Med Genet A 119A(1): 81-4. PubMed ID: 12707965
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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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