FGFR2-Related Disorders via the FGFR2 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
11331 FGFR2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11331FGFR281479 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.

For Reflex to PGxome pricing click here.

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 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Mutations in the FGFR2 gene are known to cause the following disorders: Crouzon syndrome , Pfeiffer syndrome, Jackson-Weiss syndrome, Apert syndrome, LADD syndrome , Saethre-Chotzen syndrome , Bent bone dysplasia syndrome, Axenfeld-Rieger anomaly, and a syndrome with scaphocephaly, maxillary retrusion and mental retardation. Crouzon syndrome is characterized by hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism (Vulliamy et al. 1966). Pfeiffer syndrome is characterized by coronal craniosynostosis, midface hypoplasia, and broad and medially deviated thumbs and great toes (Robin et al. 2011). Jackson-Weiss syndrome is characterized by premature fusion of the cranial sutures and radiographic anomalies of the feet, and normal hands (Heike et al. 2001; Cohen 2001). Apert syndrome is characterized by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures (Glaser et al. 2003). LADD syndrome (also called Levy-Hollister Syndrome) is the short name of Lacrimoauriculodentodigital syndrome, which is featured by abnormalities 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). Saethre-Chotzen syndrome is a craniosynostosis with low frontal hairline, facial asymmetry, brachydactyly, fifth finger clinodactyly, partial syndactyly, and vertebral column defects (Reardon and Winter 1994). Bent bone dysplasia syndrome is characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones (Merrill et al. 2012). Axenfeld–Rieger is an eye disorder featured with abnormalities of the anterior chamber angle and aqueous drainage structures, affected patients may have a high risk to develop glaucoma and iris hypoplasia, corectopia, and posterior embryotoxon. Along with eye findings, patients may present abnormalities in umbilicus, dentition, heart, or limbs (McCann et al. 2005).

Genetics

FGFR2-related disorders are inherited in an autosomal dominant manner. FGFR2 protein encoded by FGFR2 (OMIM# 176943) is a growth factor receptor, a member of the FGFR family. Like all of the FGFRs, FGFR2 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). To date, more than 100 unique causative mutations have been reported in the FGFR2 gene. These mutations are: missense (66%), splicing (13%), small insertion/deletion (18%) and only 5 gross deletion and genomic complex rearrangement (Human Gene Mutation Database; Bochukova et al. 2009). Some genotype-phenotype correlations and recurrent pathogenic mutations in FGFR2 gene have been documented, such as mutations p.Ser252Trp and p.Pro253Arg which are responsible for 98% of Apert syndrome (Bochukova et al. 2009), while p.Cys342Tyr and p.Cys342Arg are often seen in Pfeiffer or Crouzon syndrome (Rutland et al. 1995; Mulvihill et al. 1995). For Crouzon syndrome or Pfeiffer syndrome, ~80% of FGFR2 pathogenic mutations are located in exons 8 and 10, and ~10% of them are in exons 3, 5, 11, 14, 15, 16, and 17 (Robin et al. 2011). FGFR2 mutations were found in 100% patients (227 patients) with Apert syndrome: 223/227 with point mutations and 4/227 with an Alu insertion or exon deletion (Bochukova et al. 2009). A de novo mutation, c.1172T>C (p.Met391Thr), was found in three unrelated patients affected with bent bone dysplasia (Merrill et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

Generally, the sensitivity of this test should be very high, because almost 97% of known pathogenic mutations are missense, splicing site and small deletions/insertions. Only five documented pathogenic variants are large deletion/insertion (Human Gene Mutation Database; Bochukova et al. 2009). Clinical sensitivity for Apert syndrome may be ~98%, because only 4 out of 227 Apert syndrome patients with FGFR2 mutations are large deletion/insertion (Bochukova et al. 2009). Also, FGFR2 mutations were identified in 4 out of 6 families with LADD syndrome (Rohmann et al. 2006).

Testing Strategy

This test provides full coverage of all coding exons of the FGFR2 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Targeted testing should first be considered for: patients with Apert syndrome (p.Ser252Trp and p.Pro253Arg variants,) and for patients with Pfeiffer or Crouzon (p.Cys342Tyr and p.Cys342Arg variants), as well as c.1172T>C (p.Met391Thr) for patients affected with bent bone dysplasia (Mulvihill et al. 1995; Robin et al. 2011; Merrill et al. 2012).

Indications for Test

Candidates for this test are patients with symptoms consistent with FGFR2-related disorders and the family members of patients who have known FGFR2 mutations.

Gene

Official Gene Symbol OMIM ID
FGFR2 176943
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bochukova EG, Roscioli T, Hedges DJ, Taylor IB, Johnson D, David DJ, Deininger PL, Wilkie AOM. 2009. Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum. Mutat. 30: 204–211. PubMed ID: 18726952
  • Cohen MM. 2001. Jackson-Weiss syndrome. American journal of medical genetics 100: 325–329. PubMed ID: 11343324
  • Glaser RL, Broman KW, Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW. 2003. The Paternal-Age Effect in Apert Syndrome Is Due, in Part, to the Increased Frequency of Mutations in Sperm. Am J Hum Genet 73: 939–947. PubMed ID: 12900791
  • Green PJ, Walsh FS, Doherty P. 1996. Promiscuity of fibroblast growth factor receptors. Bioessays 18: 639–646. PubMed ID: 8760337
  • Heike C, Seto M, Hing A, Palidin A, Hu FZ, Preston RA, Ehrlich GD, Cunningham M. 2001. Century of Jackson-Weiss syndrome: Further definition of clinical and radiographic findings in “lost” descendants of the original kindred. American journal of medical genetics 100: 315–324. PubMed ID: 11343323
  • Human Gene Mutation Database (Bio-base).
  • McCann E, Kaye SB, Newman W, Norbury G, Black GCM, Ellis IH. 2005. Novel phenotype of craniosynostosis and ocular anterior chamber dysgenesis with a fibroblast growth factor receptor 2 mutation. American Journal of Medical Genetics Part A 138A: 278–281. PubMed ID: 16158432
  • Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, Lyons KM, Deixler H, Robinson H, Chitayat D, Curry CJ, Lachman RS, et al. 2012. Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling. Am J Hum Genet 90: 550–557. PubMed ID: 22387015
  • Mulvihill JJ. 1995. Craniofacial syndromes: no such thing as a single gene disease. Nat. Genet. 9: 101–103. PubMed ID: 7719329
  • Reardon W, Winter RM. 1994. Saethre-Chotzen syndrome. J Med Genet 31: 393–396. PubMed ID: 8064818
  • 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
  • Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nürnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, et al. 2006. Mutations in different components of FGF signaling in LADD syndrome. Nat. Genet. 38: 414–417. PubMed ID: 16501574
  • Rutland P, Pulleyn LJ, Reardon W, Baraitser M, Hayward R, Jones B, Malcolm S, Winter RM, Oldridge M, Slaney SF. 1995. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat. Genet. 9: 173–176. PubMed ID: 7719345
  • Thompson E, Pembrey M, Graham JM. 1985. Phenotypic variation in LADD syndrome. J Med Genet 22: 382–385. PubMed ID: 4078868
  • Vulliamy DG, Normandale PA. 1966. Cranio-facial Dysostosis in a Dorset Family. Arch Dis Child 41: 375–382. PubMed ID: 21032436

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.

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

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