Guidelines for investigating causality of sequence variants in human disease.

Nature 2014 Apr;508(7497):469-76

1] HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA [2] Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180223PMC
April 2014
44 Reads

Publication Analysis

Top Keywords

sequence variants
12
variants human
12
human disease
8
variants
5
reports causality
4
false-positive reports
4
causality propose
4
causality impede
4
propose guidelines
4
impede translation
4
guidelines summarizing
4
translation genomic
4
acceleration false-positive
4
standards risk
4
rigorous standards
4
summarizing confidence
4
assessing sequence
4
genomic findings
4
risk acceleration
4
confidence variant
4

References

(Supplied by CrossRef)

CJ Bell et al.
Sci. Transl. Med. 2011

Y Xue et al.
Am. J. Hum. Genet. 2012

N Norton et al.
Circ Cardiovasc Genet 2012

L Weng et al.
J. Clin. Invest. 2005

KA Hunt et al.
Nature Genet. 2012

AS Allen et al.
Nature 2013

TA Manolio et al.
Nature 2009

MJ Bamshad et al.
Nature Rev. Genet. 2011

A Kiezun et al.
Nature Genet. 2012

B Pasaniuc et al.
Nature Genet. 2012

B Li et al.
Bioinformatics 2012

Similar Publications