ESPE Abstracts (2019) 92 S11.1

Novel Insights into Developmental Pleiotropy From Genetic Studies in Kallmann Syndrome

Ravikumar Balasubramanian


Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, USA


Defects in the specification, migration and/or function of Gonadotropin-releasing hormone (GnRH) neurons gonadotropin-releasing hormone result in Kallmann Syndrome (KS), a rare genetic disorder characterized by hypogonadotropic hypogonadism and anosmia (lack of sense of smell). To identify new molecular causes of KS, we performed a systematic genetic interrogation via whole exome sequencing of KS families. Autosomal dominant loss-of-function mutations in TCF12, a transcription factor previously known to cause syndromic craniosynostosis was identified as a novel cause for KS. We observed no distinction in localization of the mutations observed in patients with KS to those previously reported with craniosynostosis. Additionally, 3/10 families display both KS and craniosynostosis indicating that TCF12 allelism per se is insufficient to explain the phenotypic variability. TCF12 now joins an emerging group of genes (FGFR1, SMCHD1, CHD7, SOX10) that result in both KS and distinct craniofacial abnormalities, suggesting a shared role of these proteins during GnRH development and craniofacial development.

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