A Diagnosis for All Rare Genetic Diseases: The Horizon and the Next Frontiers. A short commentary from Gareth Baynam

A Diagnosis for All Rare Genetic Diseases: The Horizon and the Next Frontiers.

Boycott KM, Hartley T, Biesecker LG, Gibbs RA, Innes AM, Riess O, Belmont J, Dunwoodie SL, Jojic N, Lassmann T, Mackay D, Temple IK, Visel A, Baynam G

The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances. However, to achieve the interrelated diagnostic goals of the Undiagnosed Diseases Network International and the International Rare Diseases Research Consortium (IRDiRC).

IRDiRC Goal 1 states: all patients coming to medical attention with a suspected rare disease will be diagnosed within one year if their disorder is known in the medical literature; all currently undiagnosable individuals will enter a globally coordinated diagnostic and research pipeline. Achieving this goal will require the development and implementation of strategies to understand the mechanisms underlying all rare diseases and translation of these in to clinical care.

This article focuses on the horizons and next frontiers for rare diseases diagnosis including mechanisms of rare diseases that are currently intractable to exome sequencing and analysis such as mosaicism, genomic alterations, gene regulation and complex inheritance.

Addressing these mechanisms will be critical to delivering against the diagnostic needs of those with undiagnosed diseases including for individuals that can be grouped into cohorts that include: those with no causative variants in disorders with highly specific tests; no causative variants in genetically heterogenous cohorts; unsolved recognisable disorders;  and previously undescribed disorders.

https://www.ncbi.nlm.nih.gov/pubmed/30901545