The unsolved rare genetic disease atlas? An analysis of the unexplained phenotypic descriptions in OMIM®

Abstract

For years, the genetics community has estimated the number of individual rare genetic diseases to be approximately 6,000–8,000. A commonly quoted derivation of this estimate is based on the simple addition of the number of phenotypic entries with and without confirmed molecular etiologies in the Online Mendelian Inheritance in Man (OMIM®). Here, we examine the validity of this estimation by mining the phenotypic entries in OMIM that are of likely or suspected Mendelian inheritance without a molecular cause (MIM number prefix “%” or “null”). Of the 3,204 unsolved phenotypic entries in OMIM, only two‐thirds (2,034 entries) represented rare diseases. Of these, 8% were considered “well‐established” based on their description in commonly used reference textbooks. We hypothesize based on the large proportion of entries that represent single families reported prior to 2011, that a number of the unsolved entries represent pathogenic variants in known genes. The novel gene discovery potential of these entries is therefore likely lower than originally thought. Given that the majority of the ~300 new disease‐gene associations curated each year by OMIM were never associated with a “%” or “null” sign, the true scope of the rare disease atlas is likely much larger than previously anticipated.

The burden of rare diseases

“…However, all phenotypes included in OMIM have a confirmed or suspected inherited basis, which is not true of all rare disorders (see below); on the other hand, not all phenotypes included there represent rare diseases. In fact, about two‐thirds of the unsolved phenotypic entries in OMIM represent rare diseases, while only 8% are well‐established conditions (Hartley et al, ). The website Orphadata, which extracts data sets from Orphanet, includes a list of 9,603 rare diseases (http://www.orphadata.org/data/xml/en_product1.xml, accessed October 19, 2018), and represents perhaps the most comprehensive curated list of rare diseases.…”

“…This is not a static number, since new gene‐disease associations are described regularly, with the potential to increase the aforementioned percentage. In fact, there are approximately 300 new Mendelian phenotypes added to OMIM each year, the vast majority of which represent novel gene‐disease associations (Chong et al, ; Hartley et al, ). A list of 226 rare diseases (those that represent Food and Drug Administration [FDA]‐approved indications for orphan drugs) is provided as Supporting Information Table S1; as can be appreciated, 40% of disorders in that representative list have an inherited basis, similar to the percentage of all rare diseases with a genetic basis in the larger Orphanet database.…”

Mendelian Gene Discovery: Fast and Furious with No End in Sight

“…For a small number of recessive MCs, identification of only one protein-coding variant led to the search for a non-coding variant in trans via WGS. [20][21][22][23][24] Additionally, most non-coding pathogenic variants identified to date are small to moderate-size (e.g., multiple nucleotides) deletions, insertions, mobile element, or repeat expansions and contractions that remove or alter the sequence of a large portion or all of a regulatory element, [9][10][11][12][13] duplicate the element in its entirety, 25 or translocate it out of its normal sequence context. 26,27 Enrichment for non-coding SNVs in regulatory regions has been detected in, for example, developmental disorders 28 and autism, 29 but proving the pathogenicity for any one specific SNV is challenging because most are unique and alter non-overlapping bases.…”

Unsolved recognizable patterns of human malformation: Challenges and opportunities

“…In their commentary, Hartley, Balci, Rojas, Eaton, Dyment, and Boycott mine the invaluable OMIM resource of approximately 7,000 catalogued Mendelian rare diseases. They estimate that 160 of these diseases are “well established” phenotypes that remain unsolved (Hartley et al, ). The global rare disease community would be well‐served by the study of these disorders, including, whenever possible, their originally‐described families.…”