International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Abstract

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Keywords: IRDiRC; Matchmaker Exchange; disease modeling; gene discovery; genome sequencing; ontologies; rare diseases; solving the unsolved; transcriptome sequencing.

Figure 1

Approximate Number of Gene Discoveries Made by WES and WGS versus Conventional Approaches since 2010 according to OMIM Data Since the introduction of WES and WGS in 2010, the pace of the discovery of genes underlying RGDs per year has increased, and the proportion of discoveries made by WES or WGS (blue) or by conventional approaches (red) has steadily increased. Since 2013, WES and WGS have discovered nearly three times as many genes as conventional approaches, but the rate of discovery appears to be declining. Adapted from Chong et al.

Figure 2

Approximate Number of Novel Gene-Phenotype Discoveries from 2010 to 2015 according to Ophanet Data Since 2010, the proportion of discoveries that are new disease-gene relations each year (known genes associated with a new disease) has steadily increased. Since 2013, the rate of discovery of both novel genes and new disease-gene relations appears to be declining.

Figure 3

Map of the IRDiRC The IRDiRC was formally launched in 2011 and currently includes member institutions from Asia, the Middle East, Australasia, Europe, and North America. The current cumulative commitment from the 42 member institutions from both the public and private sectors is estimated at more than $2,000,000,000 USD.