Estimating the number of diseases - the concept of rare, ultra-rare, and hyper-rare

Abstract

At the dawn of the personalized medicine era, the number of rare diseases has been estimated at 10,000. By considering the influence of environmental factors together with genetic variations and our improved diagnostic capabilities, an assessment suggests a considerably larger number. The majority would be extremely rare, and hence, we introduce the term "hyper-rare," defined as affecting <1/10⁸ individuals. Such disorders would potentially outnumber all currently known rare diseases. Because autosomal recessive disorders are likely concentrated in consanguineous populations, and rare toxicities in rural areas, establishing their existence necessitates a greater reach than is currently viable. Moreover, the randomness of X-linked and gain-of-function mutations greatly compound this challenge. However, whether concurrent diseases actually cause a distinct illness will depend on if their pathological mechanisms interact (phenotype conversion) or not (phenotype maintenance). The hyper-rare disease concept will be important in precision medicine with improved diagnosis and treatment of rare disease patients.

Keywords: Biological sciences; Clinical genetics; Genetics Disease; Health sciences; Human genetics.

Graphical abstract

Figure 1

The interaction between external factors such as environment, infection, injury, toxicity, and genetic factors causes disease Not included are allergens, which can be derived from various sources. The red cross marks a genetic disease variant, inherited or acquired.

Figure 2

Genetic variations causing disease (A) Inherited genomic polymorphisms, which individually do not cause human illness, but when combined result in polygenic disease. (B) The combination of rare, inherited, disease-causing variants together with common or rare polymorphisms, which by themselves do not cause disease. Jointly they induce a qualitatively different phenotype (phenotype conversion) as compared to the individual disorders themselves. Because the combination (disease 4) would be extremely infrequent it would qualify as hyper-rare disease. (C) Three acquired chromosomal deletions of different lengths yielding different diseases with most abnormalities being infrequent and with some being extremely rare and belonging to the hyper-rare category. Boxes indicate changes resulting in disease. Letters correspond to different chromosomes. Blue color marks a common variation; red indicates a rare variation; red cross marks genetic abnormality causing disease.

Figure 3

Estimated range in frequency and absolute number of various disease classes Left, Distinct diseases, including the concurrent coincidence of three primary immunodeficiencies, where the prevalence for chronic granulomatous disease corresponds to mutations in the autosomal NCF1 gene, encoding a 47 kDa cytosolic subunit of neutrophil NADPH oxidase. Right, the oval-shaped areas correspond to various disease classes. To compensate for that phenotype conversion only appears in certain disease combinations a correction coefficient was introduced, which for three concurrent diseases amounts to [⅓]³ = ½7.