Positional cloning of a new disease gene for normosmic hypogonadotropic hypogonadism and Kallmann syndrome using a patient with balanced chromosome translocation t(8;10)(q13;p13)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 134-163-GnRH & Gonadotroph Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-153
Hyung-Goo Kim*1, Samuel D Quaynor1, Reinhard Ullmann2, Vera M Kalscheuer2 and Lawrence C Layman1
1Georgia Regents University, Augusta, GA, 2Max Planck Institute for Molecular Genetics, Berlin, Germany
Humans with gonadotropin releasing hormone (GnRH) deficiency present with delayed sexual development, low serum gonadotropins, and low serum sex steroids. This hypogonadotropic hypogonadism may either be normosmic (nHH) or associated with anosmia or hyposmia –Kallmann syndrome (KS). At least 18 genes account for nearly 40% of the etiologies of nHH/KS; and 2-10% of patients may have mutations in two or more genes. However, the molecular basis remains unknown for the remainder of patients. Patients with nHH/KS who possess a balanced chromosomal rearrangement have been successfully utilized to identify new disease producing genes in this disorder. We have previously reported a male with adult onset nHH who has an apparently balanced chromosome translocation—46, XY,t(8;10)(q13;p13). Copy number variants were first excluded using array comparative genomic hybridization. We therefore hypothesize that a new nHH gene is disrupted or dysregulated by one breakpoint in this translocation patient. By performing array painting, both breakpoints at 8q13 and 10p13 were mapped. The breakpoint on 10p was actually located at 10p12.1 rather than 10p13. Similarly, the breakpoint at 8q13 by cytogenetics was localized more precisely to 8q12.1 by molecular analysis. These findings suggest that positional candidate genes disrupted or dysregulated by the breakpoints on these derivative chromosomes could be causative for the phenotype. Further mutation screening of these genes in nHH/KS patients without chromosomal anomalies is ongoing to confirm a potentially new causative gene for hypogonadotropic hypogonadism.

1. Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D,       Rosenberger G, Ozata M, Bick DP, Sherins RJ, Nagase T, Tekin M, Kim SH, Kim CH, Ropers HH, Gusella JF, Kalscheuer V, Choi CY and Layman LC. WDR11, a WD Protein that Interacts with Transcription Factor       EMX1, Is Mutated in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome. Am J Hum Genet   2010; 87(4):465-479.2. Hyung-Goo Kim, Hyun-Taek Kim, Natalia T. Leach, Fei Lan, Reinhard Ullmann, Asli Silahtaroglu, Ingo        Kurth, Anja Nowka, Ihn Sik Seong, Yiping Shen, Michael E. Talkowski, Douglas Ruderfer, Ji-Hyun Lee, Caron Glotzbach, Kyungsoo Ha, Susanne Kjaergaard, Alex V. Levin, Bernd F. Romeike, Tjitske Kleefstra, Oliver       Bartsch, Sarah H. Elsea, Ethylin Wang Jabs, Marcy E. MacDonald, David J. Harris, Bradley J. Quade, Hans-    Hilger Ropers, Lisa G. Shaffer, Kerstin Kutsche, Lawrence C. Layman, Niels Tommerup, Vera M. Kalscheuer,   Yang Shi, Cynthia C. Morton, Cheol-Hee Kim, James F. Gusella. Translocations disrupting PHF21A in the        Potocki-Shaffer syndrome region are associated with intellectual disability and craniofacial anomalies.      Am J Hum Genet 2012; 91(1): 56-72. 3. Kim HG*, Kishikawa S* (*equally contributed), Higgins A, Seong IS, Donovan D, Shen Y, Lally E, Weiss    L, Najm J, Kutsche K, Descartes M, Holt L, Braddock S, Troxell R, Kaplan L, Volkmar F, Klin A, Tsatsanis        K, Noens I, Pauls D, Daly MJ, MacDonald ME, Morton CC, Quad BJ, Gusella JF.  Disruption of neurexin 1 associated with autism specrum disorder. Am J Hum Genet 2008; 82(1):199-207.    4. Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick    DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC. Mutations in CHD7, Encoding a Chromatin-        Remodeling Protein,Cause Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome. Am J Hum Genet 2008; 83(4):511-519. 5. Hyung-Goo Kim, Balasubramanian Bhagavath, Lawrence C. Layman. Clinical Manifestations of Impaired GnRH Neuron Development and Function. Neurosignals 2008;16(2-3):165-182.

Nothing to Disclose: HGK, SDQ, RU, VMK, LCL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: 5RO1 HD033004-14