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Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies

Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies
Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies
Next generation sequencing has revolutionised rare disease diagnostics. Concomitant with advancing technologies has been a rise in the number of new gene disorders discovered and diagnoses made for patients and their families. However, despite the trend towards whole exome and whole genome sequencing, diagnostic rates remain suboptimal. On average, only ~30% of patients receive a molecular diagnosis. National sequencing projects launched in the last five years are integrating clinical diagnostic testing with research avenues to widen the spectrum of known genetic disorders. Consequently, efforts to diagnose genetic disorders in a clinical setting are now often shared with efforts to prioritise candidate variants for the detection of new disease genes.

Herein we discuss some of the biggest obstacles precluding molecular diagnosis and discovery of new gene disorders. We consider bioinformatic and analytical challenges faced when interpreting next generation sequencing data and showcase some of the newest tools available to mitigate these issues. We consider how incomplete penetrance, non-coding variation and structural variants are likely to impact diagnostic rates and we further discuss methods for uplifting novel gene discovery by adopting a gene-to-patient based approach.
diagnostic odyssey, diagnostics, exome sequencing, genomics, novel gene discovery, rare disease
2041-2649
243-258
Seaby, Eleanor Grace
f9011f96-bbc5-4364-970a-0f510489c539
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Seaby, Eleanor Grace
f9011f96-bbc5-4364-970a-0f510489c539
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Seaby, Eleanor Grace and Ennis, Sarah (2020) Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies. Briefings in Functional Genomics, 19 (4), 243-258. (doi:10.1093/bfgp/elaa009).

Record type: Article

Abstract

Next generation sequencing has revolutionised rare disease diagnostics. Concomitant with advancing technologies has been a rise in the number of new gene disorders discovered and diagnoses made for patients and their families. However, despite the trend towards whole exome and whole genome sequencing, diagnostic rates remain suboptimal. On average, only ~30% of patients receive a molecular diagnosis. National sequencing projects launched in the last five years are integrating clinical diagnostic testing with research avenues to widen the spectrum of known genetic disorders. Consequently, efforts to diagnose genetic disorders in a clinical setting are now often shared with efforts to prioritise candidate variants for the detection of new disease genes.

Herein we discuss some of the biggest obstacles precluding molecular diagnosis and discovery of new gene disorders. We consider bioinformatic and analytical challenges faced when interpreting next generation sequencing data and showcase some of the newest tools available to mitigate these issues. We consider how incomplete penetrance, non-coding variation and structural variants are likely to impact diagnostic rates and we further discuss methods for uplifting novel gene discovery by adopting a gene-to-patient based approach.

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BFG review accepted - Accepted Manuscript
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More information

Accepted/In Press date: 13 March 2020
e-pub ahead of print date: 12 May 2020
Keywords: diagnostic odyssey, diagnostics, exome sequencing, genomics, novel gene discovery, rare disease

Identifiers

Local EPrints ID: 439749
URI: http://eprints.soton.ac.uk/id/eprint/439749
ISSN: 2041-2649
PURE UUID: 2109004a-6edd-4509-a6b4-89a7a1235652
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 01 May 2020 16:36
Last modified: 22 Nov 2021 08:07

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Contributors

Author: Eleanor Grace Seaby
Author: Sarah Ennis ORCID iD

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