Interactome-Based Affiliation Scoring (IBAS) is a Novel Bioinformatic Tool to Identify and Prioritize Candidate Genes: Validation study in Congenital Hypogonadotropic Hypogonadism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 112-141-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-125
Hichem Miraoui*1, Andrew A Dwyer1, Gerasimos Sykiotis2, Lacey C Plummer3, Wilson C J Chung4, Bihua Feng3, Andrew Beenken5, Jeff Carke6, Tune H Pers7, Piotr Dworzynski7, Kimberly Woodward Keefe3, Marek Niedziela8, Taneli J. M. Raivio9, William F Crowley Jr.3, Stephanie Beth Seminara*3, Richard Quinton10, Virginia A Hughes1, Filip Kumanov11, Jacques Young12, Maria A Yialamas13, Janet Elizabeth Hall3, Jean-Pierre Chanoine14, John Rubenstein6, Moosa Mohammadi5, Pei-San Tsai15, Yisrael Sidis1, Nelly Pitteloud1 and Kasper Lage7
1Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, 2University of Patras Medical Sch, Patras, Greece, 3Massachusetts General Hospital, Boston, MA, 4Kent State University, Kent, OH, 5New York University School of Medicine, New York, NY, 6University of California at San Francisco, San Francisco, CA, 7Technical University of Denmark, Lyngby, Denmark, 8Poznan University of Medical Sci, Poznan, Poland, 9Institute of Biomedicine/Physiology, Helsinki, Finland, 10Newcastle-upon-Tyne Hospitals, Newcastle Upon Tyne, United Kingdom, 11Med Univ, Sofija, Bulgaria, 12Hospital BicÍtre-Univ Paris Sud, Le Kremlin Bicetre, France, 13Brigham and Women's Hospital, Boston, MA, 14British Columbia Children's Hospital, Vancouver, BC, Canada, 15Univ of Colorado, Boulder, CO
Background: Congenital hypogonadotropic hypogonadism (CHH) can be associated with anosmia (Kallmann syndrome, KS). CHH is genetically heterogeneous with more than 15 genes implicated. FGF8 and FGFR1 account for ~12%; notably, the CHH genes KAL1 and HS6TSO1 are also involved in FGFR1 signaling. We therefore hypothesized that a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier genes.

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

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: National Insitutes of Health RO1 HD056264 & U54 HD028138, Swiss National Science Foundation #31003A-135648, and COST Action BM1105