Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.

Nat Genet 2017 Apr 13;49(4):504-510. Epub 2017 Feb 13.

Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496244PMC
April 2017
65 Reads

Publication Analysis

Top Keywords

neurodevelopmental disorders
12
excess inherited
8
novo variation
8
novo variants
8
protein-truncating variants
8
lof-intolerant genes
8
role novo
8
novo protein-truncating
8
novo
6
variants
5
resides lower-penetrant
4
contribute neurodevelopmental
4
risk loss-of-function
4
neurodevelopmental risk
4
risk resides
4
metric pli
4
lof-intolerance metric
4
variants contribute
4
loss-of-function lof-intolerance
4
60706 adults
4

References

(Supplied by CrossRef)
Article in Nat. Genet.
SH Lee et al.
Nat. Genet. 2013
Article in Nat. Genet.
T Gaugler et al.
Nat. Genet. 2014
Article in Mol. Autism
L Klei et al.
Mol. Autism 2012
Article in Nature
S De Rubeis et al.
Nature 2014
Article in Nature
I Iossifov et al.
Nature 2014
Article in Neuron
I Iossifov et al.
Neuron 2012
Article in Nature
BM Neale et al.
Nature 2012
Article in Nature
BJ O'Roak et al.
Nature 2012
Article in Nature
SJ Sanders et al.
Nature 2012
Article in Proc. Natl. Acad. Sci. USA
A Reichenberg et al.
Proc. Natl. Acad. Sci. USA 2016
Article in N. Engl. J. Med.
J de Ligt et al.
N. Engl. J. Med. 2012

Similar Publications