Deciphering the Role of Copy Number Variants in Neuroendocrine Disorders of Infertility

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PROJECT ABSTRACT Despite 6-12% of women and men around the world suffering from infertility, the full ensemble of genes that control human reproduction has not been fully characterized. In this study, the PI will study the genetic background of Idiopathic Hypogonadotropic Hypogonadism (IHH), a rare neuroendocrine disorder caused by defects in Gonadotropin Releasing Hormone (GnRH) neuronal signaling, that leads to delayed puberty and infertility. The genetic etiology in 60% of IHH patients remains unknown. This missing heritability can be attributed to poor characterization of elusive genetic variation such as copy number variants (CNVs) that are hard to capture using traditional sequencing technologies, such as karyotypes and microarrays. Recent advantages in next generation sequencing have allowed detection of smaller CNVs from exome sequencing (ES) data. In this study, the PI will utilize such cutting edge CNV calling algorithms in a large cohort of IHH subjects (1,400) to examine the contribution of CNVs to the missing heritability of IHH, understand the GnRH neuronal biology and decipher the genetic control of rare and common reproductive disorders. The PI will explore the contribution of CNVs to known and novel IHH genes and will utilize human phenotypes from the IHH patients and subjects enrolled to the Mass General Brigham biobank (in whom CNVs from ES will be called) to determine the consequences of CNVs in human disease expression. The PI will complete the proposed work under the mentorship of Dr. Seminara, Dr. Talkowski and Dr. Balasubramanian. Dr. Seminara is the PI of a NICHD- sponsored P50 National Center of Translational Research in Reproduction and Infertility (NCTRI) – Center for Reproductive Medicine (CRM) at the Massachusetts General Hospital (MGH) and will provide all available resources (access to ES and phenotypic databases) for the successful completion of his research proposal as well as direct mentorship to facilitate her transition to an independent career as a physician scientist. Dr. Talkowski is the Director for the Center of Genomic Medicine (CGM) at MGH and has pioneered novel CNV approaches. Under his guidance, the PI will analyze ES derived CNVs in IHH, control and biobank subjects. Dr. Talkowski is also the Director of the Genomics Core that houses all the resources for the functional validation of the novel genes that will emerge from the PI’s CNV analyses (IPSc derived GnRH cells). Finally, Dr. Balasubramanian is the Assistant Director of the NCTRI-CRM with significant expertise in studying population biobanks for human genetic investigations and will provide important guidance to the PI for the successful completion of her proposal. In addition, the candidate will pursue formal coursework and regular engagement in research meetings related to both reproductive endocrinology and genetics. This project will facilitate development of skills in the areas of clinical investigation and human genetics and represents a comprehensive plan to identify the role of CNVs in rare inherited neuroendocrine disorders of infertility, preparing the PI to apply for a career development award to continue her training to become an independent clinical investigator.