SAT-LB071 Loss of Function (LoF) mutations in TCF12 Cause Autosomal Dominant Kallmann Syndrome and Reveal Network-level Interactions Between Causal Loci

• Published in: Journal of the Endocrine Society 2019-04, Vol.3 (Supplement_1)
• Main Authors: Keefe, David, Balasubramanian, Ravikumar, Davis, Erica, Kupchinsky, Zachary, Plummer, Lacey, Meczekalski, Blazej, Heath, Karen, Margabanthu, Gomathi, Price, Susan, Greening, James, Wierman, Margaret, Crowley, William, Katsanis, Nicholas
• Format: Article
• Language: English
• Subjects: Neuroendocrinology and Pituitary
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/js.2019-SAT-LB071

Dysfunction of Gonadotropin-releasing hormone (GnRH) causes a range of reproductive disorders resulting from defects in the specification, migration and/or function of GnRH neurons. To identify new genetic and molecular components of this system, we performed whole exome sequencing (WES) of families with Isolated GnRH deficiency (IGD). We report 10 families with anosmic form of IGD (i.e, Kallmann Syndrome; [KS]) harboring autosomal dominant LoF mutations in TCF12 , a transcription factor also known to cause syndromic craniosynostosis. No apparent distinction in mutation localization on the TCF12 locus for KS vs the reported craniosynostosis alleles occurred. Additionally, 3/10 families display both KS and craniosynostosis indicating that allelism at the driver gene alone is insufficient to explain the phenotypic variability. To dissect this phenomenon further, we showed that loss of tcf12 in zebrafish perturbs GnRH neuronal patterning with concomitant attenuation of the expression of several genes that potentially lie ‘downstream’ that are both mutated in other syndromic forms of IGD and map to a TCF12 affinity network. Finally, rescue of the LoF mutations of tcf 12 was achieved by mRNA corresponding to one of these loci, STUB1 . In addition to extending the rapidly evolving genetic architecture of IGD, these studies begin to assemble one of the functional networks that regulate the ontogeny of GnRH neurons and potentially modulate phenotype. These findings also highlight an emerging class of pleiotropic genes that contribute to IGD and craniofacial development like FGFR1, SMCHD1, CHD7 , and now TCF12 . Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.