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Genes 2019, 10(4), 275; https://doi.org/10.3390/genes10040275

Uncovering Missing Heritability in Rare Diseases

1
Departments of Biochemistry, Molecular Biology and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
2
Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
*
Author to whom correspondence should be addressed.
Received: 1 March 2019 / Revised: 29 March 2019 / Accepted: 1 April 2019 / Published: 4 April 2019
(This article belongs to the Special Issue Bioinformatic Analysis for Rare Diseases)
PDF [458 KB, uploaded 4 April 2019]

Abstract

The problem of ‘missing heritability’ affects both common and rare diseases hindering: discovery, diagnosis, and patient care. The ‘missing heritability’ concept has been mainly associated with common and complex diseases where promising modern technological advances, like genome-wide association studies (GWAS), were unable to uncover the complete genetic mechanism of the disease/trait. Although rare diseases (RDs) have low prevalence individually, collectively they are common. Furthermore, multi-level genetic and phenotypic complexity when combined with the individual rarity of these conditions poses an important challenge in the quest to identify causative genetic changes in RD patients. In recent years, high throughput sequencing has accelerated discovery and diagnosis in RDs. However, despite the several-fold increase (from ~10% using traditional to ~40% using genome-wide genetic testing) in finding genetic causes of these diseases in RD patients, as is the case in common diseases—the majority of RDs are also facing the ‘missing heritability’ problem. This review outlines the key role of high throughput sequencing in uncovering genetics behind RDs, with a particular focus on genome sequencing. We review current advances and challenges of sequencing technologies, bioinformatics approaches, and resources.
Keywords: missing heritability; rare disease; genome sequencing; long/short read sequencing; bioinformatics; variant detection; variant annotation; variation databases missing heritability; rare disease; genome sequencing; long/short read sequencing; bioinformatics; variant detection; variant annotation; variation databases
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Maroilley, T.; Tarailo-Graovac, M. Uncovering Missing Heritability in Rare Diseases. Genes 2019, 10, 275.

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