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FGFR3-Related Disorders via the FGFR3 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
9245 FGFR3 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9245FGFR381479 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

  • Juan Dong, PhD, FACMG

Clinical Features and Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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).

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

Testing Strategy

This test provides full coverage of all coding exons of the FGFR3 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).

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 via the MSX2 Gene
Frontonasal Dysplasia (Frontorhiny) via the ALX3 Gene
Hypochondroplasia via the FGFR3 Gene
Thanatophoric Dysplasia (TD) via the FGFR3 Gene

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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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

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

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1) Select Test Method (Backbone)


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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.
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