The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1

• Published in: Journal of dental research Vol. 96; no. 11; pp. 1339 - 1345
• Main Authors: Lansdon, L.A., Bernabe, H.V., Nidey, N., Standley, J., Schnieders, M.J., Murray, J.C.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.10.2017; SAGE PUBLICATIONS, INC
• Subjects: Adult; Age; Cleft Lip - genetics; Cleft lip/palate; Cleft Palate - genetics; Congenital defects; Congenital diseases; Corpus callosum; Craniofacial Abnormalities - genetics; Data analysis; Dentistry; Deoxyribonucleic acid; Diabetes; Diabetes insipidus; Disulfide bonds; DNA; Ectrodactyly; Fibroblast growth factor receptor 1; Fibroblast growth factor receptors; Fingers - abnormalities; Gene mapping; Genetic Association Studies; Genetic Variation; Genotype; Genotype & phenotype; Genotypes; Hand Deformities, Congenital - genetics; Holoprosencephaly; Holoprosencephaly - genetics; Humans; Intellectual Disability - genetics; Kinases; Male; Mutation; Mutation, Missense; Phenotype; Phenotypes; Protein folding; Protein structure; Proteins; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Research Reports; Ventricle; Ventricles (cerebral); X-rays; craniofacial biology/genetics; clinical phenotypes; genetics; craniofacial anomalies; protein modeling; Hartsfield syndrome
• ISSN: 0022-0345; 1544-0591
• DOI: 10.1177/0022034517726496

Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.