Neurodevelopmental Disease Genes Implicated by De Novo Mutation and Copy Number Variation Morbidity

Overview

Journal Nat Genet

Specialty Genetics

Date 2018 Dec 19

PMID 30559488

Citations 153

Authors

Bradley P Coe

Holly A F 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

Affiliations

Soon will be listed here.

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) 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.

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References

Panjwani D, BALL M, Berry N, Wimperis J, Blacklock H, Prentice H . Virological and serological diagnosis of cytomegalovirus infection in bone marrow allograft recipients. J Med Virol. 1985; 16(4):357-65. DOI: 10.1002/jmv.1890160409. View

Sharp A, Locke D, McGrath S, Cheng Z, Bailey J, Vallente R . Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. 2005; 77(1):78-88. PMC: 1226196. DOI: 10.1086/431652. View

Tuzun E, Sharp A, Bailey J, Kaul R, Morrison V, Pertz L . Fine-scale structural variation of the human genome. Nat Genet. 2005; 37(7):727-32. DOI: 10.1038/ng1562. View

de Vries B, Pfundt R, Leisink M, Koolen D, Vissers L, Janssen I . Diagnostic genome profiling in mental retardation. Am J Hum Genet. 2005; 77(4):606-16. PMC: 1275609. DOI: 10.1086/491719. View

Bailey J, Yavor A, Massa H, Trask B, Eichler E . Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 2001; 11(6):1005-17. PMC: 311093. DOI: 10.1101/gr.gr-1871r. View

de Vries B, White S, Knight S, Regan R, Homfray T, Young I . Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J Med Genet. 2001; 38(3):145-50. PMC: 1734836. DOI: 10.1136/jmg.38.3.145. View

Firth H, Wright C . The Deciphering Developmental Disorders (DDD) study. Dev Med Child Neurol. 2011; 53(8):702-3. DOI: 10.1111/j.1469-8749.2011.04032.x. View

ORoak B, Deriziotis P, Lee C, Vives L, Schwartz J, Girirajan S . Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011; 43(6):585-9. PMC: 3115696. DOI: 10.1038/ng.835. View

Stessman H, Xiong B, Coe B, Wang T, Hoekzema K, Fenckova M . Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017; 49(4):515-526. PMC: 5374041. DOI: 10.1038/ng.3792. View

10.

ORoak B, Vives L, Fu W, Egertson J, Stanaway I, Phelps I . Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012; 338(6114):1619-22. PMC: 3528801. DOI: 10.1126/science.1227764. View

11.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

12.

Turner T, Douville C, Kim D, Stenson P, Cooper D, Chakravarti A . Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns. Hum Mol Genet. 2015; 24(21):5995-6002. PMC: 6354780. DOI: 10.1093/hmg/ddv309. View

13.

Geisheker M, Heymann G, Wang T, Coe B, Turner T, Stessman H . Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci. 2017; 20(8):1043-1051. PMC: 5539915. DOI: 10.1038/nn.4589. View

14.

Lelieveld S, Wiel L, Venselaar H, Pfundt R, Vriend G, Veltman J . Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. Am J Hum Genet. 2017; 101(3):478-484. PMC: 5591029. DOI: 10.1016/j.ajhg.2017.08.004. View

15.

Cooper G, Coe B, Girirajan S, Rosenfeld J, Vu T, Baker C . A copy number variation morbidity map of developmental delay. Nat Genet. 2011; 43(9):838-46. PMC: 3171215. DOI: 10.1038/ng.909. View

16.

Kaminsky E, Kaul V, Paschall J, Church D, Bunke B, Kunig D . An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011; 13(9):777-84. PMC: 3661946. DOI: 10.1097/GIM.0b013e31822c79f9. View

17.

Coe B, Witherspoon K, Rosenfeld J, van Bon B, Vulto-van Silfhout A, Bosco P . Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014; 46(10):1063-71. PMC: 4177294. DOI: 10.1038/ng.3092. View

18.

Turner T, Yi Q, Krumm N, Huddleston J, Hoekzema K, Stessman H . denovo-db: a compendium of human de novo variants. Nucleic Acids Res. 2016; 45(D1):D804-D811. PMC: 5210614. DOI: 10.1093/nar/gkw865. View

19.

Matson J, Shoemaker M . Intellectual disability and its relationship to autism spectrum disorders. Res Dev Disabil. 2009; 30(6):1107-14. DOI: 10.1016/j.ridd.2009.06.003. View

20.

Iossifov I, ORoak B, Sanders S, Ronemus M, Krumm N, Levy D . The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515(7526):216-21. PMC: 4313871. DOI: 10.1038/nature13908. View