Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era.

Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD utilizing different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. While such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation-sequencing (NGS), are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to:1) look back at the strategies used to discover the “known” genes implicated in the rare forms of IGD 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation, 3) substantiate the role of “known” genes in the pathophysiology of the disease and 4) project forward as we embark upon a widening utilization of these new and powerful technologies for gene discovery.

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