FGFR1-Related Disorders via the FGFR1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
498 FGFR1$990.00 81405 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

FGFR1 mutations were detected in nine of 80  patients with congenital hypogonadotropic hypogonadism with and without anosmia (Trarbach et al. 2006). One study reported that six unique FGFR1 pathogenic missense mutations were found in seven unrelated patients affected with Hartsfield syndrome (Simonis et al. 2013). Only 4 large deletions and genomic complex rearrangements involving FGFR1 were reported in patients affected with Kallmann syndrome or related disorders (Fukami et al. 2013)

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FGFR1$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Mutations in the FGFR1 gene are known to cause multiple disorders. Pfeiffer syndrome is characterized by coronal craniosynostosis, midface hypoplasia, and broad and medially deviated thumbs and great toes (Robin et al. 2011). Trigonocephaly is a disorder caused by premature closure of the metopic sutures (Azimi et al. 2002). Osteoglophonic dysplasia is characterized by rhizomelic dwarfism with depression of the nasal bridge, frontal bossing, and prognathism (Farrow 2006). 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 et al. 2001). Hartsfield syndrome is characterized by holoprosencephaly, ectrodactyly, with or without cleft/lip palate. Some patients may also present profound mental retardation and midline and limb defects (Vilain et al. 2009). Mutations in FGFR1 comprise ~5% of pathogenic mutations in Pfeiffer syndrome (Robin et al. 2011) and ~10% of pathogenic mutations in Kallman syndrome (Buck et al. 2013). Kallmann syndrome patients with FGFR1 mutations may show incomplete penetrance (Buck et al. 2013). Kallmann syndrome type II (also called hypogonadotropic hypogonadism-2 with or without anosmia (HH2) belongs to a group of heterogeneous disorders called isolated gonadotropin-releasing hormone (GnRH) deficiency, which is characterized by absent or incomplete sexual maturation by the age of 18 years. Patients  have low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Some non-reproductive features include cleft palate, mirror movements, and dental agenesis. Most HH2 patients with FGFR1 mutations were anosmic or hyposmic (Trarbach et al. 2006; Buck et al. 2013).


Hartsfield syndrome caused by mutations in FGFR1 is inherited in both an autosomal dominant and recessive manner (Simonis et al. 2013), while FGFR1-related Pfeiffer syndrome, Trigonocephaly, Osteoglophonic dysplasia, Jackson-Weiss syndrome and Kallmann syndrome are inherited in an autosomal dominant manner. FGFR1 protein encoded by FGFR1 (OMIM# 136350) is a growth factor receptor and a member of the FGFR family. Like all of the FGFRs, FGFR1 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 150 unique causative mutations have been reported in the FGFR1 gene. These mutations are: missense (70%), nonsense (7%), splicing (7%),  small insertion/deletion (13%) and only 4 gross deletions and genomic complex rearrangements (Human Gene Mutation Database). The majority (~90%) of reported pathogenic mutations in the FGFR1 gene are found in patients affected with Kallmann or Kallmann-related disorders (Human Gene Mutation Database). Six of the missense mutations were found in patients affected with Hartsfield syndrome. Only a few disease causing FGFR1 mutations were reported in other FGFR1-related disorders, such as the c.755C>G (p.Pro252Arg) variant reported to cause Pfeiffer syndrome.

Testing Strategy

FGFR1 protein is coded by exons 4, 6 to 21 of the FGFR1 gene on chromosome 8p11.2. Testing involves PCR amplifications from genomic DNA and bidirectional Sanger sequencing of the coding exons and ~20bp of adjacent noncoding sequences. We will also sequence any single exon (Test#100) or pair of exons (Test#200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Candidates for this test are patients with symptoms consistent with FGFR1-related disorders and the family members of patients who have known FGFR1 mutations.


Official Gene Symbol OMIM ID
FGFR1 136350
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Craniosynostosis and Related Disorders Sequencing Panel
Facial Dysostosis Related Disorders Sequencing Panel


Genetic Counselors
  • Azimi C, Kennedy SJ, Chitayat D, Chakraborty P, Clarke JTR, Forrest C, Teebi AS. 2002. Clinical and genetic aspects of trigonocephaly: A study of 25 cases. American Journal of Medical Genetics Part A 117A: 127–135. PubMed ID: 12567409
  • Buck C, Balasubramanian R, Crowley WF. 2013. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 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: 20301509
  • Cohen MM. 2001. Jackson-Weiss syndrome. American journal of medical genetics 100: 325–329. PubMed ID: 11343324
  • Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, Pitukcheewanont P, White KE. 2006. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. American Journal of Medical Genetics Part A 140A: 537–539. PubMed ID: 16470795
  • Fukami M, Iso M, Sato N, Igarashi M, Seo M, Kazukawa I, Kinoshita E, Dateki S, Ogata T. 2013. Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. Endocr. J. 60: 1013–1020. PubMed ID: 23657145
  • 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).
  • 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
  • Simonis N, Migeotte I, Lambert N, Perazzolo C, Silva DC de, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Vliet G Van, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C. 2013. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. Journal of Medical Genetics 50: 585–592. PubMed ID: 23812909
  • Trarbach EB, Costa EMF, Versiani B, Castro M de, Baptista MTM, Garmes HM, Mendonca BB de, Latronico AC. 2006. Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia. Journal of Clinical Endocrinology & Metabolism 91: 4006–4012. PubMed ID: 16882753
  • Vilain C, Mortier G, Vliet G Van, Dubourg C, Heinrichs C, Silva D de, Verloes A, Baumann C. 2009. Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: Further delineation and review. American Journal of Medical Genetics Part A 149A: 1476–1481. PubMed ID: 19504604
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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.

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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.
  • 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.


(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.


(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.


(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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