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. 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
  2. Bober, MB, et al. Hypochondroplasia. 1999 Jul 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301650
  3. 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
  4. 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
  5. Karczeski, B, Cutting, GR. Thanatophoric Dysplasia. 2004 May 21. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301540
  6. Kruszka, P, et al. Muenke syndrome: An international multicenter natural history study. Am. J. Med. Genet. A. 2016; :None. PMID: 26740388
  7. 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
  8. 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
  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. 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

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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