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Journal of Neurodevelopmental Disorders
Published in: Journal of Neurodevelopmental Disorders 1/2019

Open Access 01-12-2019 | Autism Spectrum Disorder | Research

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Authors: Gregory Costain, Susan Walker, Bob Argiropoulos, Danielle A. Baribeau, Anne S. Bassett, Erik Boot, Koen Devriendt, Barbara Kellam, Christian R. Marshall, Aparna Prasad, Moises A. Serrano, D. James Stavropoulos, Hope Twede, Joris R. Vermeesch, Jacob A. S. Vorstman, Stephen W. Scherer

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2019

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Abstract

Background

Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs.

Methods

We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases.

Results

We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs.

Conclusions

Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.
Literature
1.
Yuen RKC, Merico D, Bookman M, Howe LJ, Thiruvahindrapuram B, Patel RV, Whitney J, Deflaux N, Bingham J, Wang Z, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci. 2017;20(4):602–11.PubMedCentralCrossRef
2.
Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, Yuen RK, Uddin M, Roberts W, Weksberg R, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314(9):895–903.PubMedCrossRef
3.
Yuen RK, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, Hoang N, Chrysler C, Nalpathamkalam T, Pellecchia G, Liu Y, et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med. 2015;21(2):185–91.PubMedCrossRef
4.
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–15.PubMedPubMedCentralCrossRef
5.
Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216–21.PubMedPubMedCentralCrossRef
6.
Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, et al. Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015;47(6):582–8.PubMedPubMedCentralCrossRef
7.
Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, Pinto D, Lau L, Nalpathamkalam T, Marshall CR, et al. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet. 2014;46(7):742–7.PubMedCrossRef
8.
Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, Stefansson H, Stefansson K, Magnusson P, Gudmundsson OO, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010;376(9750):1401–8.PubMedPubMedCentralCrossRef
9.
Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, Gazzellone M, Carson AR, Howe JL, Wang Z, et al. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med. 2011;3(95):95ra75.PubMedCrossRef
10.
Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.PubMedPubMedCentralCrossRef
11.
Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43(9):838–46.PubMedPubMedCentralCrossRef
12.
Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511(7509):344–7.PubMedCrossRef
13.
Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, Levy S, Gogos JA, Karayiorgou M. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 2012;44(12):1365–9.PubMedPubMedCentralCrossRef
14.
Costain G, Lionel AC, Merico D, Forsythe P, Russell K, Lowther C, Yuen T, Husted J, Stavropoulos DJ, Speevak M, et al. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. Hum Mol Genet. 2013;22(22):4485–501.PubMedPubMedCentralCrossRef
15.
Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H, Consortium on the Genetics of S, Group PS, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013;154(3):518–29.PubMedPubMedCentralCrossRef
16.
Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, Georgieva L, Rees E, Palta P, Ruderfer DM, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179–84.PubMedPubMedCentralCrossRef
17.
Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, Antaki D, Shetty A, Holmans PA, Pinto D, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49(1):27–35.PubMedCrossRef
18.
Cook EH Jr, Scherer SW. Copy-number variations associated with neuropsychiatric conditions. Nature. 2008;455(7215):919–23.PubMedCrossRef
19.
20.
Hehir-Kwa JY, Pfundt R, Veltman JA. Exome sequencing and whole genome sequencing for the detection of copy number variation. Expert Rev Mol Diagn. 2015;15(8):1023–32.PubMedCrossRef
21.
Vorstman JA, Ophoff RA. Genetic causes of developmental disorders. Curr Opin Neurol. 2013;26(2):128–36.PubMedCrossRef
22.
Lowther C, Costain G, Baribeau DA, Bassett AS. Genomic disorders in psychiatry-what does the clinician need to know? Curr Psychiatry Rep. 2017;19(11):82.PubMedCrossRef
23.
Woodbury-Smith M, Paterson AD, Thiruvahindrapduram B, Lionel AC, Marshall CR, Merico D, Fernandez BA, Duku E, Sutcliffe JS, O'Conner I, et al. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes. Hum Genet. 2015;134(2):191–201.PubMedCrossRef
24.
Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Thiruvahindrapuram B, Merico D, Jobling R, Nalpathamkalam T, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018;20(4):435–43.PubMedCrossRef
25.
Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G, Yuen RKC, Szego MJ, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012.
26.
Noll AC, Miller NA, Smith LD, Yoo B, Fiedler S, Cooley LD, Willig LK, Petrikin JE, Cakici J, Lesko J, et al. Clinical detection of deletion structural variants in whole-genome sequences. NPJ Genom Med. 2016;1:16026.PubMedPubMedCentralCrossRef
27.
Buchanan JA, Scherer SW. Contemplating effects of genomic structural variation. Genet Med. 2008;10(9):639–47.PubMedCrossRef
28.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.PubMedPubMedCentralCrossRef
29.
Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061–73.CrossRef
30.
Tennessen JA, Bigham AW, O'Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337(6090):64–9.PubMedPubMedCentralCrossRef
31.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.PubMedPubMedCentralCrossRef
32.
Zhu M, Need AC, Han Y, Ge D, Maia JM, Zhu Q, Heinzen EL, Cirulli ET, Pelak K, He M, et al. Using ERDS to infer copy-number variants in high-coverage genomes. Am J Hum Genet. 2012;91(3):408–21.PubMedPubMedCentralCrossRef
33.
Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21(6):974–84.PubMedPubMedCentralCrossRef
34.
Trost B, Walker S, Wang Z, Thiruvahindrapuram B, MacDonald JR, Sung WWL, Pereira SL, Whitney J, Chan AJS, Pellecchia G, et al. A comprehensive workflow for read depth-based identification of copy-number variation from whole-genome sequence data. Am J Hum Genet. 2018;102(1):142–55.PubMedPubMedCentralCrossRef
35.
MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42(Database issue):D986–92.PubMedCrossRef
36.
Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015;16(3):172–83.PubMedCrossRef
37.
Uddin M, Thiruvahindrapuram B, Walker S, Wang Z, Hu P, Lamoureux S, Wei J, MacDonald JR, Pellecchia G, Lu C, et al. A high-resolution copy-number variation resource for clinical and population genetics. Genet Med. 2015;17(9):747–52.PubMedCrossRef
38.
Uddin M, Pellecchia G, Thiruvahindrapuram B, D’Abate L, Merico D, Chan A, Zarrei M, Tammimies K, Walker S, Gazzellone MJ, et al. Indexing effects of copy number variation on genes involved in developmental delay. Sci Rep. 2016;6:28663.PubMedPubMedCentralCrossRef
39.
Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP. DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am J Hum Genet. 2009;84(4):524–33.PubMedPubMedCentralCrossRef
40.
Iverson GL, Woodward TS, Green P. Base rates of WAIS-R VIQ-PIQ differences in 1593 psychiatric inpatients. J Clin Psychol. 2001;57(12):1579–87.PubMedCrossRef
41.
Chen DY, Liu XF, Lin XJ, Zhang D, Chai YC, Yu DH, Sun CL, Wang XL, Zhu WD, Chen Y, et al. A dominant variant in DMXL2 is linked to nonsyndromic hearing loss. Genet Med. 2017;19(5):553–8.CrossRefPubMed
42.
Tata B, Huijbregts L, Jacquier S, Csaba Z, Genin E, Meyer V, Leka S, Dupont J, Charles P, Chevenne D, et al. Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse. PLoS Biol. 2014;12(9):e1001952.PubMedPubMedCentralCrossRef
43.
Bayes A, van de Lagemaat LN, Collins MO, Croning MD, Whittle IR, Choudhary JS, Grant SG. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci. 2011;14(1):19–21.PubMedCrossRef
44.
Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature. 2012;492(7429):382–6.PubMedPubMedCentralCrossRef
45.
Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146(2):247–61.PubMedPubMedCentralCrossRef
46.
Pirooznia M, Wang T, Avramopoulos D, Potash JB, Zandi PP, Goes FS. High-throughput sequencing of the synaptome in major depressive disorder. Mol Psychiatry. 2016;21(5):650–5.PubMedCrossRef
47.
Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I, Bermingham JR Jr, Peles E. Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron. 2005;47(2):215–29.PubMedCrossRef
48.
Maluenda J, Manso C, Quevarec L, Vivanti A, Marguet F, Gonzales M, Guimiot F, Petit F, Toutain A, Whalen S, et al. Mutations in GLDN, encoding Gliomedin, a critical component of the nodes of Ranvier, are responsible for lethal arthrogryposis. Am J Hum Genet. 2016;99(4):928–33.PubMedPubMedCentralCrossRef
49.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.PubMedPubMedCentralCrossRef
50.
Griswold AJ, Ma D, Cukier HN, Nations LD, Schmidt MA, Chung RH, Jaworski JM, Salyakina D, Konidari I, Whitehead PL, et al. Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. Hum Mol Genet. 2012;21(15):3513–23.PubMedPubMedCentralCrossRef
51.
Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, et al. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet. 2012;131(4):565–79.PubMedCrossRef
52.
Takenouchi T, Hashida N, Torii C, Kosaki R, Takahashi T, Kosaki K. 1p34.3 deletion involving GRIK3: further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay. Am J Med Genet A. 2014;164A(2):456–60.PubMedCrossRef
53.
Aller MI, Pecoraro V, Paternain AV, Canals S, Lerma J. Increased dosage of high-affinity kainate receptor gene grik4 alters synaptic transmission and reproduces autism spectrum disorders features. J Neurosci. 2015;35(40):13619–28.PubMedCrossRefPubMedCentral
54.
Micheau J, Vimeney A, Normand E, Mulle C, Riedel G. Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice. Hippocampus. 2014;24(9):1059–69.PubMedCrossRef
55.
Bienkowski RS, Banerjee A, Rounds JC, Rha J, Omotade OF, Gross C, Morris KJ, Leung SW, Pak C, Jones SK, et al. The conserved, disease-associated RNA binding protein dNab2 interacts with the fragile X protein ortholog in Drosophila neurons. Cell Rep. 2017;20(6):1372–84.PubMedPubMedCentralCrossRef
56.
Rha J, Jones SK, Fidler J, Banerjee A, Leung SW, Morris KJ, Wong JC, Inglis GAS, Shapiro L, Deng Q, et al. The RNA-binding protein, ZC3H14, is required for proper poly(A) tail length control, expression of synaptic proteins, and brain function in mice. Hum Mol Genet. 2017;26(19):3663–81.PubMedPubMedCentralCrossRef
57.
Pak C, Garshasbi M, Kahrizi K, Gross C, Apponi LH, Noto JJ, Kelly SM, Leung SW, Tzschach A, Behjati F, et al. Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans. Proc Natl Acad Sci U S A. 2011;108(30):12390–5.PubMedPubMedCentralCrossRef
58.
59.
Tempesta S, Sollima D, Ghezzo S, Politi V, Sinigaglia B, Balducci F, Celso B, Restuccia A, Stefani M, Cernetti R, et al. Mild mental retardation in a child with a de novo interstitial deletion of 15q21.2q22.1: a comparison with previously described cases. Eur J Med Genet. 2008;51(6):639–45.PubMedCrossRef
60.
Velazquez-Wong AC, Ruiz Esparza-Garrido R, Velazquez-Flores MA, Huicochea-Montiel JC, Cardenas-Conejo A, Miguez-Munoz CP, Araujo-Solis MA, Salamanca-Gomez F, Arenas-Aranda DJ. Clinical and molecular characterization of a patient with 15q21.2q22.2 deletion syndrome. Cytogenet Genome Res. 2014;144(3):183–9.PubMedCrossRef
61.
Vorstman JAS, Parr JR, Moreno-De-Luca D, Anney RJL, Nurnberger JI Jr, Hallmayer JF. Autism genetics: opportunities and challenges for clinical translation. Nat Rev Genet. 2017;18(6):362–76.PubMedCrossRef
62.
Takumi T, Tamada K. CNV biology in neurodevelopmental disorders. Curr Opin Neurobiol. 2018;48:183–92.PubMedCrossRef
63.
Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, O'Connor I, Russell C, Drmic IE, Hamdan FF, et al. SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012;90(5):879–87.PubMedPubMedCentralCrossRef
64.
Lowther C, Costain G, Melvin R, Stavropoulos DJ, Lionel AC, Marshall CR, Scherer SW, Bassett AS. Adult expression of a 3q13.31 microdeletion. Mol Cytogenet. 2014;7(1):23.PubMedPubMedCentralCrossRef
65.
Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med. 2012;367(14):1321–31.PubMedPubMedCentralCrossRef
66.
Bassett AS, Lowther C, Merico D, Costain G, Chow EWC, van Amelsvoort T, McDonald-McGinn D, Gur RE, Swillen A, Van den Bree M, et al. Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome. Am J Psychiatry. 2017;174(11):1054–63.PubMedPubMedCentralCrossRef
67.
Tata BK, Harbulot C, Csaba Z, Peineau S, Jacquier S, de Roux N. Rabconnectin-3alpha is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness. Sci Rep. 2017;7:42463.PubMedPubMedCentralCrossRef
68.
Kannan M, Bayam E, Wagner C, Rinaldi B, Kretz PF, Tilly P, Roos M, McGillewie L, Bar S, Minocha S, et al. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy. Proc Natl Acad Sci U S A. 2017;114(44):E9308–17.PubMedPubMedCentralCrossRef
69.
Li KW, Chen N, Klemmer P, Koopmans F, Karupothula R, Smit AB. Identifying true protein complex constituents in interaction proteomics: the example of the DMXL2 protein complex. Proteomics. 2012;12(15–16):2428–32.PubMed
70.
Abekhoukh S, Bardoni B. CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome. Front Cell Neurosci. 2014;8:81.PubMedPubMedCentralCrossRef
71.
Nakashima M, Kato M, Aoto K, Shiina M, Belal H, Mukaida S, Kumada S, Sato A, Zerem A, Lerman-Sagie T, et al. De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann Neurol. 2018;83(4):794–806.PubMedCrossRef
72.
Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C, Parrini E, Valence S, Pierre BS, Oger M, et al. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet. 2013;45(6):639–47.CrossRefPubMed
73.
Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371(8):733–43.PubMedPubMedCentralCrossRef
74.
Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, Pliner HA, Abramzon Y, Marangi G, Winborn BJ, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17(5):664–6.PubMedPubMedCentralCrossRef
75.
Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, Shamseldin HE, AlZahrani F, Patel N, Ibrahim N, et al. Expanding the genetic heterogeneity of intellectual disability. Hum Genet. 2017;136(11–12):1419–29.PubMedCrossRef
76.
77.
Han K, Chen H, Gennarino VA, Richman R, Lu HC, Zoghbi HY. Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice. Hum Mol Genet. 2015;24(7):1813–23.PubMedCrossRef
78.
De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A, Ostroff LE, Klann E, Zwartkruis FJ, Komiyama NH, et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron. 2013;79(6):1169–82.PubMedPubMedCentralCrossRef
79.
80.
81.
Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680–5.PubMedCrossRef
82.
Merico D, Zarrei M, Costain G, Ogura L, Alipanahi B, Gazzellone MJ, Butcher NJ, Thiruvahindrapuram B, Nalpathamkalam T, Chow EW, et al. Whole-genome sequencing suggests schizophrenia risk mechanisms in humans with 22q11.2 deletion syndrome. G3 (Bethesda). 2015;5(11):2453–61.CrossRef
83.
Niemi MEK, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, McAloney K, McRae J, Radford EJ, Yu S, et al. Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature. 2018;562(7726):268–71.PubMedCrossRefPubMedCentral
84.
Vermeesch JR, Balikova I, Schrander-Stumpel C, Fryns JP, Devriendt K. The causality of de novo copy number variants is overestimated. Eur J Hum Genet. 2011;19(11):1112–3.PubMedPubMedCentralCrossRef
85.
Costain G. Parental expression is overvalued in the interpretation of rare inherited variants. Eur J Hum Genet. 2015;23(1):4–7.PubMedCrossRef
86.
Giorgio E, Ciolfi A, Biamino E, Caputo V, Di Gregorio E, Belligni EF, Calcia A, Gaidolfi E, Bruselles A, Mancini C, et al. Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: two proof-of-concept examples. Am J Med Genet A. 2016;170(7):1772–9.PubMedCrossRef
87.
88.
Tsiplova K, Zur RM, Marshall CR, Stavropoulos DJ, Pereira SL, Merico D, Young EJ, Sung WWL, Scherer SW, Ungar WJ. A microcosting and cost-consequence analysis of clinical genomic testing strategies in autism spectrum disorder. Genet Med. 2017;19(11):1268–75.PubMedCrossRef
Metadata
Title
Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders
Authors
Gregory Costain
Susan Walker
Bob Argiropoulos
Danielle A. Baribeau
Anne S. Bassett
Erik Boot
Koen Devriendt
Barbara Kellam
Christian R. Marshall
Aparna Prasad
Moises A. Serrano
D. James Stavropoulos
Hope Twede
Joris R. Vermeesch
Jacob A. S. Vorstman
Stephen W. Scherer
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neurodevelopmental Disorders / Issue 1/2019
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI
https://doi.org/10.1186/s11689-019-9263-3

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