Annotating rare variants: A challenge that has not been completely resolved

Since the mid-1980s, the combination of clinical research into rare diseases and rapid advances in molecular genetics has led to major breakthroughs in the molecular diagnosis and management of these conditions, which sometimes affect only a small number of patients. These advances have been made possible by considerable investment in understanding the structure of the genome. Techniques have been greatly simplified over the past 20 years, and whole genome sequencing is now performed as part of patient care. Major advances have thus been made in the interest of patients, but new challenges have also emerged. The limiting factor is no longer knowing the sequence of a patient's genome, but rather confirming the link between a specific DNA variant and the phenotype. The more we advance in this understanding, the more we realize that the simplest situations are now well understood. The purpose of this article is to briefly review the organization of the human genome and the difficulties encountered in confirming the pathogenicity of a variant, using the example of congenital gonadotropin deficiency.