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FGFR2-Related Disorders via the FGFR2 Gene

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

NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4667 FGFR2$690.00 81479 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
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 28 days.

Clinical Sensitivity

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FGFR2$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

Only five documented pathogenic variants are large deletions/insertions (Human Gene Mutation Database; Bochukova et al. 2009).

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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).

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing. 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

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CONTACTS

Genetic Counselors
Geneticist
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
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most 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 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.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

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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