FGFR1-Related Disorders via the FGFR1 Gene

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.

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).

This test provides full coverage of all coding exons of the FGFR1 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).