• Test code: 04729
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae FGFR3-Related Disorders Test

Test description

This test analyzes the FGFR3 gene, which is associated with a wide range of phenotypes affecting the skeletal system, including skeletal dysplasias and craniosynostosis syndrome. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (1 gene)

Alternative tests to consider

The Invitae Craniosynostosis Panel has been designed to provide a broad genetic analysis of this class of disorders and may be considered as an alternative to testing for FGFR3-related conditions. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.

  • achondroplasia
  • camptodactyly, tall stature, and hearing loss (CATSHL) syndrome
  • Crouzon syndrome with acanthosis nigricans
  • hypochondroplasia
  • lacrimo-auriculo-dento-digital (LADD) syndrome
  • Muenke syndrome
  • severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)
  • thanatophoric dysplasia

The disorders associated with the FGFR3 gene can broadly be described as skeletal dysplasias and craniosynostosis syndromes. Skeletal dysplasias are disorders involving abnormalities in the growth and development of the skeletal system; they often involve unusual stature and other skeletal anomalies. Craniosynostosis syndromes involve early fusion of the cranial sutures, affect individual or multiple sutures, and may be either isolated or in occurrence with additional congenital anomalies.

Approximately 98% of cases of achondroplasia are attributed to the variant p.Gly380Arg in FGFR3, and 65%–87% of cases of hypochondroplasia are caused by the c.1620C>A (p.Asn540Lys) variant in FGFR3. FGFR3 can also cause some cases of lacrimo-auriculo-dento-digital (LADD) syndrome although the proportion of disease caused by variants in the FGFR3 gene is unknown. Greater than 99% of cases of thanatophoric dysplasia are attributed to variants in the FGFR3 gene.

FGFR3-related disorders are inherited in an autosomal dominant manner. De novo variants in FGFR3 are well described.

Penetrance of FGFR3-related disorders varies by disorders but is generally high.

Achondroplasia occurs in an estimated 1 in 26,000–28,000 live births. Hypochondroplasia is a relatively common skeletal dysplasia that may approach the prevalence of achondroplasia. Muenke syndrome occurs in an estimated 1 in 30,000 births.

Thanatophoric dysplasia occurs in approximately 1 in 20,000 live births, though in the Northern Irish population, prevalence has been estimated at 1 in 12,000 live births.

Prevalence of camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Crouzon syndrome with acanthosis nigricans, lacrimo-auriculo-dento-digital (LADD) syndrome, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are unknown.

  1. Oberklaid, F, et al. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J. Med. Genet. 1979; 16(2):140-6. PMID: 458831
  2. Orioli, IM, et al. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am. J. Med. Genet. 1995; 59(2):209-17. PMID: 8588588
  3. Bober, MB, et al. Hypochondroplasia. 1999 Jul 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301650
  4. Kruszka, P, et al. Muenke syndrome: An international multicenter natural history study. Am. J. Med. Genet. A. 2016; :None. PMID: 26740388
  5. Barbosa-Buck, CO, et al. Clinical epidemiology of skeletal dysplasias in South America. Am. J. Med. Genet. A. 2012; 158A(5):1038-45. PMID: 22407836
  6. Donnelly, DE, et al. The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study. Ulster Med J. 2010; 79(3):114-8. PMID: 22375084
  7. Heuertz, S, et al. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. Eur. J. Hum. Genet. 2006; 14(12):1240-7. PMID: 16912704
  8. Shiang, R, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994; 78(2):335-42. PMID: 7913883
  9. Schweitzer, DN, et al. Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3. Am. J. Med. Genet. 2001; 98(1):75-91. PMID: 11426459
  10. Karczeski, B, Cutting, GR. Thanatophoric Dysplasia. 2004 May 21. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301540

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
FGFR3 NM_000142.4