Session: MON 112-141-Hypothalamus-Pituitary Development & Biology
Poster Board MON-125
Aims: We aimed: (i) to investigate whether CHH patients harbor rare sequence variants in members of the so-called “FGF8 synexpression” group; and (ii) to validate the ability of a new bioinformatics tool based on protein-protein interactome data to identify high-quality candidate genes.
Methods & Results: Based on sequence homology, expression, and structural and functional data, 7 genes were selected, and sequenced in 386 unrelated CHH patients and in 155 controls. Except for FGF18 and SPRY2, all other genes were found to harbor rare sequence variants in CHH patients: FGF17 (n=3 patients), IL17RD (n=8), DUSP6 (n=5), SPRY4 (n=14) and FLRT3 (n=3). Independently, a new algorithm “interactome-based affiliation scoring” (IBAS) predicted FGF17 and IL17RD as the two most likely candidates in the entire proteome based on a statistical test of their protein-protein interaction patterns to known CHH proteins; most of the FGF17 and IL17RD mutants alter protein function. IL17RD mutations were found only in KS and were strongly linked to hearing loss (6/8 patients).
Conclusions: IBAS correctly identified FGF17 and IL17RD as the two most promising candidate genes in the entire proteome (12,507 proteins for which we have interaction data). Patient mutations identified in the CHH cohort validate IBAS as an accurate and useful bioinformatic tool for gene discovery. The new FGF pathway mutations are associated with complex modes of CHH inheritance and act primarily as contributors to the oligogenicity of this disease. IBAS may be applied to other genetic disorders and may have additional future applications such as filtering exome data to identify high quality candidates.
Nothing to Disclose: HM, AAD, GS, LCP, WCJC, BF, AB, JC, THP, PD, KWK, MN, TJMR, WFC Jr., SBS, RQ, VAH, FK, JY, MAY, JEH, JPC, JR, MM, PST, YS, NP, KL
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