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FGFR3-Related Disorders 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
429 FGFR3$970.00 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
FGFR3 pathogenic variants were found in >99% of patients with Achondroplasia, Thanatophoric dysplasia and Muenke syndrome; and ~70% of patients with hypochondroplasia. For Crouzon syndrome with acanthosis nigricans, targeted testing for p.Ala391Glu should first be considered. Clinical sensitivity for other FGFR3-related disorders is currently unknown (Pauli, 2012;Bober et al. 2013; Karczeski and Cutting 2013; Agochukwu et al. 2014; Robin et al. 2011).

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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 Sensitivity
To date, no gross deletions or duplications have been reported in FGFR3 (Human Gene Mutation Database).

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Clinical Features
FGFR3 pathogenic variants cause multiple clinical conditions. Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features with frontal bossing and mid-face retrusion (Pauli 2012). Skeletal features of Hypochondroplasia are similar to achondroplasia, but usually milder; patients with hypochondroplasia show failure to grow as toddlers or school-age (Bober et al. 2013). Thanatophoric dysplasia is a perinatal lethal short-limb dwarfism syndrome, which is divided into two subtypes: type I is characterized by micromelia with bowed femurs and usually without cloverleaf skull deformity; and type II is characterized by micromelia with straight femurs, moderate-to-severe cloverleaf skull deformity (Karczeski and Cutting 2013). Other features of thanatophoric dysplasia are: short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported. CATSHL syndrome is characterized by camptodactyly, tall stature and hearing loss; some less common features include kyphoscoliosis, mental retardation, learning disabilities, and microcephaly (Toydemir et al. 2006). LADD syndrome (also called Levy-Hollister Syndrome) is the short name of Lacrimoauriculodentodigital syndrome, which is characterized by defects of the nasal lacrimal ducts, cup-shaped pinnas with mixed hearing deficit, small and peg-shaped lateral maxillary incisors and mild enamel dysplasia and fifth finger clinodactyly, duplication of the distal phalanx of the thumb, triphalangeal thumb, and syndactyly (Thompson et al. 1985). Muenke syndrome is characterized by uni- or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay, other features include temporal bossing; widely spaced eyes, ptosis or proptosis (usually mild); midface retrusion; and highly arched palate or cleft lip and palate. Strabismus is common (Agochukwu et al. 2014).
Genetics
All FGFR3-related disorders are inherited in an autosomal dominant manner, and the majority of cases result from de novo pathogenic variants caused by gain of functional variants. An exception is FGFR3-related CATSHL syndrome,which can be inherited either in an autosomal dominant manner or autosomal recessive manner through loss of function variants in the FGFR3 gene. The 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. 1996). Some genotype-phenotype correlations have been well established. For example, most cases of achondroplasia are caused by one of two variants (c.1138G>A, p.Gly380Arg /c.1138G>C, p.Gly380Arg) in exon 10 (Shiang et al. 1994; Bellus et al. 1995; Deng et al. 1996). ~70% of Hypochondroplasia cases are caused by two variants (c.1620C>A, p.Asn540Lys and c.1620C>G, p.Asn540Lys) in exon 13 (Bellus et al. 1995; Prinos et al. 1995). Thanatophoric dysplasia type II is caused by the pathogenic variant c.1948A>G (p.Lys650Glu) in exon 15 (Bellus et al. 2000); and Muenke syndrome is caused by the c.749C>G, p.Pro250Arg variant in exon 7. Crouzon syndrome with acanthosis nigricans is caused by the pathogenic variant c.1172C>A, p. Ala391Glu in exon 10. In addition, two variants were found in two large families with CATSHL syndrome: heterozygous c.1862G>A, p.Arg621His in a family with autosomal dominant inheritance of CATSHL syndrome (Toydemir et al. 2006) and homozygous c.1637C>A, p.Thr546Lys in a family with autosomal recessive inheritance of CATSHL syndrome, respectively (Makrythanasis et al. 2014).
Testing Strategy
This test involves bidirectional sequencing using genomic DNA of all coding exons ( exons 2 to 19) 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.

Targeted testing should be considered if patient is clinically suspected to have one of the following conditions (see Table below)

Clinical Diagnosis                              Exon        Pathogenic Variants
Achondroplasia                                    10          c.1138G>A or c.1138G>C (p.Gly380Arg)
Hypochondroplasia                             13          c.1620C>A or c.1620C>G (p.Asn540Lys)
Thanatophoric dysplasia Type II       15          c.1948A>G, (p.Lys650Glu)
Muenke syndrome                                 7          c.749C>G, (p.Pro250Arg)
Crouzon syndrome                              10          c.1172C>A, (p. Ala391Glu) with acanthosis nigricans
Indications for Test
Candidates for this test include patients with clinical and radiographic features suggestive of FGFR3-related disorders.

Gene

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

Related Tests

Name
Achondroplasia via the FGFR3 Gene, Exon 10
Craniofrontonasal Syndrome via the EFNB1 Gene
Craniosynostosis and Dental Anomalies, Autosomal Recessive Crouzon-like Craniosynostosis via the IL11RA Gene
Craniosynostosis and Related Disorders Sequencing Panel
Craniosynostosis via the MSX2 Gene
Facial Dysostosis Related Disorders Sequencing Panel
Frontonasal Dysplasia (Frontorhiny) via the ALX3 Gene
Hypochondroplasia via the FGFR3 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
  • Agochukwu NB, Doherty ES, Muenke M. 2014. Muenke Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301588
  • Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, Kaitila I, McIntosh I, Francomano CA. 1995. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56: 368-373. PubMed ID: 7847369
  • 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 GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. 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: 1411–1421. PubMed ID: 11055896
  • Bober MB, Bellus GA, Nikkel SM, Tiller GE. 2013. Hypochondroplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301650
  • Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P. 1996. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84: 911-921. PubMed ID: 8601314
  • Green PJ, Walsh FS, Doherty P. 1996. Promiscuity of fibroblast growth factor receptors. Bioessays 18: 639–646. PubMed ID: 8760337
  • Human Gene Mutation Database (Bio-base).
  • Karczeski B, Cutting GR. 2013. Thanatophoric Dysplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301540
  • Makrythanasis P, Temtamy S, Aglan MS, Otaify GA, Hamamy H, Antonarakis SE. 2014. A Novel Homozygous Mutation in FGFR3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly. Human Mutation 35: 959-963. PubMed ID: 24864036
  • Pauli RM. 2012. Achondroplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301331
  • 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
  • Robin NH, Falk MJ, Haldeman-Englert CR. 2011. FGFR-Related Craniosynostosis Syndromes. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301628
  • Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335–342. PubMed ID: 7913883
  • Thompson E, Pembrey M, Graham JM. 1985. Phenotypic variation in LADD syndrome. J. Med. Genet. 22: 382-385. PubMed ID: 4078868
  • Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB, Whitby FG, Longo N, Viskochil DH, Carey JC, Bamshad MJ. 2006. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am. J. Hum. Genet. 79: 935-941. PubMed ID: 17033969
Order Kits
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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