Document Type

Article

Publication Date

8-2022

Publication Title

Human mutation

Keywords

JGM, Exome, Genomics, Humans, Phenotype, Rare Diseases, Whole Exome Sequencing

JAX Source

Hum Mutat 2022 Aug; 43(8):1071-1081

Volume

43

Issue

8

First Page

1071

Last Page

1081

ISSN

1098-1004

PMID

35391505

DOI

https://doi.org/10.1002/humu.24380

Abstract

Rare disease diagnostics and disease gene discovery have been revolutionized by whole-exome and genome sequencing but identifying the causative variant(s) from the millions in each individual remains challenging. The use of deep phenotyping of patients and reference genotype-phenotype knowledge, alongside variant data such as allele frequency, segregation, and predicted pathogenicity, has proved an effective strategy to tackle this issue. Here we review the numerous tools that have been developed to automate this approach and demonstrate the power of such an approach on several thousand diagnosed cases from the 100,000 Genomes Project. Finally, we discuss the challenges that need to be overcome if we are going to improve detection rates and help the majority of patients that still remain without a molecular diagnosis after state-of-the-art genomic interpretation.

Comments

This study was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License.

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