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Prioritization of neurodevelopmental disease genes by discovery of new mutations

Abstract

Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience.

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Figure 1: Genes with recurrent de novo mutations in four neurodevelopmental disorders.
Figure 2: CNV and exome intersections define candidate genes.
Figure 3: Phenotypic similarity of two patients with identical PACS1 de novo mutations and two patients with similar ADNP mutations.
Figure 4: Examples of coincidental de novo mutations in cancer and neurodevelopmental disorders.

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References

  1. de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).

    CAS  PubMed  Google Scholar 

  2. Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).

    CAS  PubMed  Google Scholar 

  3. O'Roak, B.J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Jiang, Y.-H. et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am. J. Hum. Genet. 93, 249–263 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Neale, B.M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Gulsuner, S. et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature doi:10.1038/nature12929 (2014).

  11. Allen, A.S. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

    CAS  PubMed  Google Scholar 

  12. Veltman, J.A. & Brunner, H.G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).

    CAS  PubMed  Google Scholar 

  13. Stefansson, H. et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366 (2014).

    CAS  PubMed  Google Scholar 

  14. Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Malaspina, D. et al. Advancing paternal age and the risk of schizophrenia. Arch. Gen. Psychiatry 58, 361–367 (2001).

    CAS  PubMed  Google Scholar 

  16. Hultman, C.M., Sandin, S., Levine, S.Z., Lichtenstein, P. & Reichenberg, A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol. Psychiatry 16, 1203–1212 (2011).

    CAS  PubMed  Google Scholar 

  17. McGrath, J.J. et al. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry 71, 301–309 (2014).

    PubMed  Google Scholar 

  18. Carvill, G.L. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, Y. et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N. Engl. J. Med. 369, 1502–1511 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. O'Roak, B.J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. O'Roak, B.J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. O'Roak, B.J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Cooper, G.M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kaminsky, E.B. et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13, 777–784 (2011).

    PubMed  PubMed Central  Google Scholar 

  25. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Vulto-van Silfhout, A.T. et al. Clinical significance of de novo and inherited copy number variation. Hum. Mutat. 34, 1679–1687 (2013).

    CAS  Article  PubMed  Google Scholar 

  27. Møller, R.S. et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am. J. Hum. Genet. 1165–1170 (2008).

    PubMed  Google Scholar 

  28. Huang, N., Lee, I., Marcotte, E.M. & Hurles, M.E. Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 6, e1001154 (2010).

    PubMed  PubMed Central  Google Scholar 

  29. van Bokhoven, H. & Brunner, H.G. Splitting p63. Am. J. Hum. Genet. 71, 1–13 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bowen, M.E. et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet. 7, e1002050 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tartaglia, M. & Gelb, B. Noonan syndrome and related disorders. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).

    CAS  PubMed  Google Scholar 

  32. Hoischen, A. et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat. Genet. 42, 483–485 (2010).

    CAS  PubMed  Google Scholar 

  33. Filges, I. et al. Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome. J. Med. Genet. 48, 117–122 (2011).

    CAS  PubMed  Google Scholar 

  34. Marseglia, G. et al. 372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment. Eur. J. Med. Genet. 55, 216–221 (2012).

    PubMed  Google Scholar 

  35. Kamath, B.M. et al. NOTCH2 mutations in Alagille syndrome. J. Med. Genet. 49, 138–144 (2012).

    CAS  PubMed  Google Scholar 

  36. Isidor, B. et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat. Genet. 43, 306–308 (2011).

    CAS  PubMed  Google Scholar 

  37. Simpson, M.A. et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 43, 303–305 (2011).

    CAS  PubMed  Google Scholar 

  38. Kryukov, G.V., Pennacchio, L.A. & Sunyaev, S.R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Khurana, E. et al. Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 342, 1235587 (2013).

    PubMed  PubMed Central  Google Scholar 

  40. Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Carter, H., Douville, C., Stenson, P.D., Cooper, D.N. & Karchin, R. Identifying Mendelian disease genes with the variant effect scoring tool. BMC Genomics 14 (suppl. 3), S3 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. Gilman, S.R. et al. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898–907 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Parikshak, N.N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell (in the press).

  44. Helsmoortel, C. et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46, 380–384 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Willsey, A.J. et al. Co-expression networks implicate human mid-fetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ronan, J.L., Wu, W. & Crabtree, G.R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Santen, G.W.E. et al. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum. Mutat. doi:10.1002/humu.22394 (2013).

  49. Hoischen, A. et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat. Genet. 43, 729–731 (2011).

    CAS  PubMed  Google Scholar 

  50. Gibson, W.T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Goriely, A. & Wilkie, A.O.M. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90, 175–200 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hudson, T.J. et al. International network of cancer genome projects. Nature 464, 993–998 (2010).

    CAS  PubMed  Google Scholar 

  53. Schuurs-Hoeijmakers, J.H.M. et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am. J. Hum. Genet. 91, 1122–1127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hoyer, J. et al. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am. J. Hum. Genet. 90, 565–572 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Santen, G.W.E. et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat. Genet. 44, 379–380 (2012).

    CAS  PubMed  Google Scholar 

  56. Girirajan, S. et al. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am. J. Hum. Genet. 92, 221–237 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Girirajan, S. et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321–1331 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Classen, C.F. et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum. Genet. 132, 825–841 (2013).

    CAS  PubMed  Google Scholar 

  59. Zaidi, S. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Skarnes, W.C. et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474, 337–342 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Tweedie, S. et al. FlyBase: enhancing Drosophila Gene Ontology annotations. Nucleic Acids Res. 37, D555–D559 (2009).

    CAS  PubMed  Google Scholar 

  62. Vulih-Shultzman, I. et al. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J. Pharmacol. Exp. Ther. 323, 438–449 (2007).

    CAS  PubMed  Google Scholar 

  63. van Bon, B.W.M. et al. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin. Genet. 79, 296–299 (2011).

    CAS  PubMed  Google Scholar 

  64. Fotaki, V. et al. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell. Biol. 22, 6636–6647 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Tejedor, F. et al. Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14, 287–301 (1995).

    CAS  PubMed  Google Scholar 

  66. Kettleborough, R.N.W. et al. A systematic genome-wide analysis of zebrafish protein-coding gene function. Nature 496, 494–497 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Genovese, G. et al. Using population admixture to help complete maps of the human genome. Nat. Genet. 45, 406–414 (2013).

    CAS  PubMed  Google Scholar 

  68. Sudmant, P.H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Beyer, K. et al. New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases. Neurogenetics 13, 61–72 (2012).

    CAS  PubMed  Google Scholar 

  70. Karakoc, E. et al. Detection of structural variants and indels within exome data. Nat. Methods 9, 176–178 (2012).

    CAS  Google Scholar 

  71. Fromer, M. et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am. J. Hum. Genet. 91, 597–607 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Krumm, N. et al. Transmission disequilibrium of small CNVs in simplex autism. Am. J. Hum. Genet. 93, 595–606 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lupski, J.R. Genetics. Genome mosaicism–one human, multiple genomes. Science 341, 358–359 (2013).

    CAS  PubMed  Google Scholar 

  74. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  77. Banka, S. et al. MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome. Clin. Genet. 83, 467–471 (2013).

    CAS  PubMed  Google Scholar 

  78. Huisman, S.A., Redeker, E.J.W., Maas, S.M., Mannens, M.M. & Hennekam, R.C.M. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J. Med. Genet. 50, 339–344 (2013).

    CAS  PubMed  Google Scholar 

  79. Rodríguez-Santiago, B. et al. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am. J. Hum. Genet. 87, 129–138 (2010).

    PubMed  PubMed Central  Google Scholar 

  80. Hiatt, J.B., Pritchard, C.C., Salipante, S.J., O'Roak, B.J. & Shendure, J. Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23, 843–854 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Shiroguchi, K., Jia, T.Z., Sims, P.A . & Xie, X.S. Digital RNA sequencing minimizes sequence-dependent bias and amplification noise with optimized single-molecule barcodes. Proc. Natl. Acad. Sci. USA 109, 1347–1352 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Klei, L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9 (2012).

    PubMed  PubMed Central  Google Scholar 

  83. Lee, S.H. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).

    CAS  PubMed  Google Scholar 

  84. Yu, T.W. et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77, 259–273 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Morrow, E.M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Najmabadi, H. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63 (2011).

    CAS  PubMed  Google Scholar 

  87. He, X. et al. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet. 9, e1003671 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011).

    CAS  PubMed  Google Scholar 

  89. Jacquemont, S. et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415–425 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Google Scholar 

  91. van Bon, B.W.M. et al. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur. J. Hum. Genet. 18, 163–170 (2010).

    PubMed  Google Scholar 

  92. Talkowski, M.E. et al. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89, 551–563 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Makishima, H. et al. Somatic SETBP1 mutations in myeloid malignancies. Nat. Genet. 45, 942–946 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Piazza, R. et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat. Genet. 45, 18–24 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to T. Brown and C. Gilissen for assistance during manuscript preparation, F. Kooy for early preprint access and H.G. Brunner for sharing patient photographs used in Figure 3. A.H. is supported by a ZonMW grant (916–12–095); E.E.E. is supported by a US National Institute of Mental Health grant (1R01MH101221–01) and is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Alexander Hoischen or Evan E Eichler.

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Competing interests

E.E.E. is on the scientific advisory board of DNAnexus, Inc. and was a scientific advisory board member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013).

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Glossary

Exome

The exome is the part of a genome that encodes proteins, approximately 1% of the human genome.

Trio family study

A trio family study is an analysis of probands and both of their parents. Sequencing-based trio studies often focus on de novo mutations that are present in the proband's genome, but are not detected in the genomes of his or her parents.

Proband

A proband is an individual being studied or reported on. The term is often used to refer to an individual affected with a disease or disorder, as distinct from their unaffected relatives.

de novo mutation (DNM)

A de novo mutation (DNM) is a mutation that is part of an individual's genome that is not detected in the genome of either parent (although it may have arisen from a mutation in the parental germline). With the exception of de novo mutations in monozygotic twins, or those shared by siblings as a result of germline mosaicism, most new mutations are not shared by relatives and do not contribute to heritability estimates.

Rare variant

Rare variant describes variants that are private to individuals and families. In some usage, the term rare variant is used more expansively to include all variants that are not common.

Copy number variation (CNV)

A copy number variation (CNV) is a type of submicroscopic genetic variation involving the deletion or duplication of a genomic region. Although CNVs can involve genomic segments as small as a kilobase or as large as several megabases, most CNVs detected are relatively large (100 kilobases or larger) because of the resolution of genotyping arrays; in the future, sequencing-based studies may analyze many smaller CNVs.

Mendelian disease

A Mendelian disease describes a single gene disorder that is caused by the presence of one (dominant) or two (recessive) alleles.

Next generation sequencing (NGS)

Next generation sequencing (NGS) refers to a set of technologies that sequence DNA in massively parallel ways; for example, by optically detecting the incorporation of specific bases into millions of different DNA molecules, spatially segregated on an imageable glass surface, at the same time.

Candidate gene

A candidate gene is a pre-specified gene of potential interest. Candidate gene studies are often distinguished from unbiased genome-wide studies that analyze variation in all or most genes simultaneously.

Locus

A locus is a place on a chromosome. A locus may contain one gene, multiple genes or no genes at all.

Resequencing

Resequencing is the activity of sequencing a gene or genomic segment that has already been sequenced in other members of that species; for example, to identify genetic variations within the species.

Case-control study

A case-control study is a study design that compares the distribution of a genetic or other variable between individuals affected with a disease (cases) and unaffected individuals (controls).

Single-nucleotide variant (SNV)

A single-nucleotide variant (SNV) is a DNA sequence variation occurring when a single nucleotide differs between members of a species. The term SNV is often used to describe sequence variants that are not common, or whose allele frequency is not known.

Genetic background

Genetic background refers to the genotype of all genes that may modify the expression or presentation of a phenotype related to a gene of interest.

Complex disease

A complex disease describes a disorder caused by many contributing factors, both genetic and non-genetic, and does not display a simple pattern of inheritance.

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Hoischen, A., Krumm, N. & Eichler, E. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci 17, 764–772 (2014). https://doi.org/10.1038/nn.3703

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