ABSTRACT
Success in the era of human genetic studies was first realized with the identification of rare variants underlying Mendelian forms of disease. Also termed single-gene disorders, these diseases are often the result of changes in DNA sequence (mutations) in one gene and have been observed to segregate within families. The first Mendelian disease for which the molecular basis was identified was sickle cell anemia [1]. Resulting from a nucleotide transversion (A→T), the codon at amino acid position 6 in the β-hemoglobin gene (HBB) is mutated from a glutamic acid to valine. The mutation produces a variant form of the β-chain of hemoglobin, termed HbS, which polymerizes in red blood cells after deoxygenation [2,3]. This aggregation of hemoglobin chains causes red blood cells to distort into a crescent or sickled shape. These defective red blood cells are unable to transport oxygen and cause obstructions in the vasculature, resulting in increased mortality. This discovery demonstrated a molecular basis for disease that has been successfully applied to many other Mendelian diseases (e.g., cystic fibrosis [4], Tay Sachs disease [5], and Huntington’s disease [6].) The majority of Mendelian phenotypes identified to date result from protein coding mutations, with relatively few phenotypes attributed to variation outside the coding region [7]. As of November 2017, there were 5,132 Mendelian phenotypes with a known molecular basis, while 1,593 remain unknown, and many more Mendelian conditions have yet to be recognized [8].
