Abstract
Hereditary diseases, or genetic diseases, are generally considered to be caused only by single-nucleotide mutations. Typically, the assumption is that a single mutation is solely responsible for the clinical syndrome. This perspective is common, as geneticists search for one specific nucleotide mutation or variant that can account for the clinical phenotype. However, this approach has led to an oversimplified understanding of the genetic pathology or causes of these diseases, resulting in a diagnostic gap for many hereditary conditions. Consequently, we encounter patients with apparent hereditary issues yet lack a meaningful genetic explanation. This has led to reduced diagnostic yield and is one of the main challenges for genetic counsellors. Moreover, GWAS studies have shown limited success in fully elucidating the inheritance of most of the complex traits studied, typically reaching the explained heritability of not more than 30%. These limitations have given rise to the term “missing heritability”, which signifies our inability to clarify genetic inheritance using mainstream methods. This chapter presents a potential solution to the missing heritability problem. It demonstrates that much of the heritability remains unaccounted for due to its complexity, arising from transposable or repetitive elements in the human genome. The genetic basis for heritable conditions is intricate and necessitates a sophisticated approach to reveal the parts of missing heritability.