FGFR2-Related Disorders via the FGFR2 Gene

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).

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).

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).

This test provides full coverage of all coding exons of the FGFR2 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).

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).