Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

Bradley P. Coe, Holly Stessman, Arvis Sulovari, Madeleine R. Geisheker, Trygve E. Bakken, Allison M. Lake, Joseph D. Dougherty, Ed S. Lein, Fereydoun Hormozdiari, Raphael A. Bernier, Evan E. Eichler

Research output: Contribution to journalArticle

Abstract

We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10−7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.

Original languageEnglish (US)
Pages (from-to)106-116
Number of pages11
JournalNature genetics
Volume51
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Morbidity
Mutation
Genes
Chromosome Duplication
Exome
Gene Regulatory Networks
Missense Mutation
Autistic Disorder
Neurons
Trisomy 2q37 Chromosome 2
Chromosome 2q37 deletion syndrome

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Coe, B. P., Stessman, H., Sulovari, A., Geisheker, M. R., Bakken, T. E., Lake, A. M., ... Eichler, E. E. (2019). Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nature genetics, 51(1), 106-116. https://doi.org/10.1038/s41588-018-0288-4

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. / Coe, Bradley P.; Stessman, Holly; Sulovari, Arvis; Geisheker, Madeleine R.; Bakken, Trygve E.; Lake, Allison M.; Dougherty, Joseph D.; Lein, Ed S.; Hormozdiari, Fereydoun; Bernier, Raphael A.; Eichler, Evan E.

In: Nature genetics, Vol. 51, No. 1, 01.01.2019, p. 106-116.

Research output: Contribution to journalArticle

Coe, BP, Stessman, H, Sulovari, A, Geisheker, MR, Bakken, TE, Lake, AM, Dougherty, JD, Lein, ES, Hormozdiari, F, Bernier, RA & Eichler, EE 2019, 'Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity', Nature genetics, vol. 51, no. 1, pp. 106-116. https://doi.org/10.1038/s41588-018-0288-4
Coe, Bradley P. ; Stessman, Holly ; Sulovari, Arvis ; Geisheker, Madeleine R. ; Bakken, Trygve E. ; Lake, Allison M. ; Dougherty, Joseph D. ; Lein, Ed S. ; Hormozdiari, Fereydoun ; Bernier, Raphael A. ; Eichler, Evan E. / Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. In: Nature genetics. 2019 ; Vol. 51, No. 1. pp. 106-116.
@article{192ae1fe2e644d638f10ee9d2c4c124c,
title = "Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity",
abstract = "We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10−7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.",
author = "Coe, {Bradley P.} and Holly Stessman and Arvis Sulovari and Geisheker, {Madeleine R.} and Bakken, {Trygve E.} and Lake, {Allison M.} and Dougherty, {Joseph D.} and Lein, {Ed S.} and Fereydoun Hormozdiari and Bernier, {Raphael A.} and Eichler, {Evan E.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41588-018-0288-4",
language = "English (US)",
volume = "51",
pages = "106--116",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

AU - Coe, Bradley P.

AU - Stessman, Holly

AU - Sulovari, Arvis

AU - Geisheker, Madeleine R.

AU - Bakken, Trygve E.

AU - Lake, Allison M.

AU - Dougherty, Joseph D.

AU - Lein, Ed S.

AU - Hormozdiari, Fereydoun

AU - Bernier, Raphael A.

AU - Eichler, Evan E.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10−7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.

AB - We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10−7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.

UR - http://www.scopus.com/inward/record.url?scp=85058847706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058847706&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0288-4

DO - 10.1038/s41588-018-0288-4

M3 - Article

VL - 51

SP - 106

EP - 116

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -