Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder
Carregando...
Citações na Scopus
3
Tipo de produção
article
Data de publicação
2017
Título da Revista
ISSN da Revista
Título do Volume
Editora
PUBLIC LIBRARY SCIENCE
Autores
KITAJIMA, Joao Paulo
FOCK, Rodrigo Ambrosio
SIMOES, Sergio Nery
KREPISCHI, Ana C. V.
ROSENBERG, Carla
LOURENCO, Naila Cristina
Citação
PLOS ONE, v.12, n.1, article ID e0170386, 22p, 2017
Resumo
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations D single nucleotide variants (SNVs) or small insertions and deletions (indels) D with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings' shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.
Palavras-chave
Referências
- Abrahams BS, 2008, NAT REV GENET, V9, P341, DOI 10.1038/nrg2346
- Altmann A, 2012, HUM GENET, V131, P1541, DOI 10.1007/s00439-012-1213-z
- American Psychiatric Association, 2013, DIAGN STAT MAN MENT
- Andrews T, 2015, GENOME RES, V25, P802, DOI 10.1101/gr.184325.114
- Anney R, 2012, HUM MOL GENET, V21, P4781, DOI 10.1093/hmg/dds301
- Barabasi AL, 2011, NAT REV GENET, V12, P56, DOI 10.1038/nrg2918
- Benvenuto A, 2009, INT J PEDIAT, V2009, P1, DOI 10.1155/2009/198736
- Berghs S, 2000, J CELL BIOL, V151, P985, DOI 10.1083/jcb.151.5.985
- Bi C, 2012, HUM MUTAT, V33, P1635, DOI 10.1002/humu.22174
- Bosse K, 2004, ANN GENET-PARIS, V47, P191, DOI 10.1016/j.anngen.2004.02.004
- Bremer A, 2011, AM J MED GENET B, V156B, P115, DOI 10.1002/ajmg.b.31142
- Burnside RD, 2013, AM J MED GENET A, V161A, P822, DOI 10.1002/ajmg.a.35699
- Cai JJ, 2010, GENOME BIOL EVOL, V2, P815, DOI 10.1093/gbe/evq064
- Chang BS, 2007, AM J MED GENET B, V144B, P58, DOI 10.1002/ajmg.b.30392
- Cho YR, 2010, BMC BIOINFORMATICS, V11, DOI 10.1186/1471-2105-11-S3-S3
- Cooper GM, 2011, NAT GENET, V43, P838, DOI 10.1038/ng.909
- Cyr AB, 2011, AM J MED GENET A, V155A, P2224, DOI 10.1002/ajmg.a.34120
- Davydov EV, 2010, PLOS COMPUT BIOL, V6, DOI 10.1371/journal.pcbi.1001025
- Delezoide AL, 1998, MECH DEVELOP, V77, P19, DOI 10.1016/S0925-4773(98)00133-6
- Delvecchio G, 2015, AM J MED GENET B, V168, P188, DOI 10.1002/ajmg.b.32294
- DePristo MA, 2011, NAT GENET, V43, P491, DOI 10.1038/ng.806
- Devlin B, 2012, CURR OPIN GENET DEV, V22, P229, DOI 10.1016/j.gde.2012.03.002
- Fatemi SH, 2000, MOL PSYCHIATR, V5, P654, DOI 10.1038/sj.mp.4000783
- Fombonne E, 2003, JAMA-J AM MED ASSOC, V289, P87, DOI 10.1001/jama.289.1.87
- Geschwind DH, 2007, CURR OPIN NEUROBIOL, V17, P103, DOI 10.1016/j.conb.2007.01.009
- Geschwind DH, 2015, SCIENCE, V349, P1489, DOI 10.1126/science.aaa8954
- Giglio S, 2002, AM J HUM GENET, V71, P276, DOI 10.1086/341610
- Gilman SR, 2011, NEURON, V70, P898, DOI 10.1016/j.neuron.2011.05.021
- Glessner JT, 2009, NATURE, V459, P569, DOI 10.1038/nature07953
- Goes FS, 2010, AM J MED GENET B, V153B, P549, DOI 10.1002/ajmg.b.31018
- GOGGIN M, 1993, BRIT J OPHTHALMOL, V77, P122, DOI 10.1136/bjo.77.2.122
- Graves LM, 2000, NATURE, V403, P328, DOI 10.1038/35002111
- Grayton HM, 2012, PROG NEUROBIOL, V99, P81, DOI 10.1016/j.pneurobio.2012.07.005
- Haas CA, 2002, J NEUROSCI, V22, P5797
- Hallmayer J, 2011, ARCH GEN PSYCHIAT, V68, P1095, DOI 10.1001/archgenpsychiatry.2011.76
- Hemmat M, 2013, MOL CYTOGENET, V6, DOI 10.1186/1755-8166-6-17
- Hori H, 2014, J AFFECT DISORDERS, V158, P90, DOI 10.1016/j.jad.2014.02.008
- Iossifov I, 2014, NATURE, V515, P216, DOI 10.1038/nature13908
- Iossifov I, 2012, NEURON, V74, P285, DOI 10.1016/j.neuron.2012.04.009
- Iqbal Z, 2013, HUM MOL GENET, V22, P1960, DOI 10.1093/hmg/ddt043
- Itan Y, 2015, P NATL ACAD SCI USA, V112, P11426, DOI 10.1073/pnas.1515057112
- Itsara A, 2009, AM J HUM GENET, V84, P148, DOI 10.1016/j.ajhg.2008.12.014
- Jacquemont ML, 2006, J MED GENET, V43, P843, DOI 10.1136/jmg.2006.043166
- Jensen LJ, 2009, NUCLEIC ACIDS RES, V37, pD412, DOI 10.1093/nar/gkn760
- Klei L, 2012, MOL AUTISM, V3, DOI 10.1186/2040-2392-3-9
- Krejci P, 2014, MUTAT RES-REV MUTAT, V759, P40, DOI 10.1016/j.mrrev.2013.11.001
- Krumm N, 2013, TRENDS NEUROSCI, V37, P1
- Krumm N, 2015, NAT GENET, V47, P582, DOI 10.1038/ng.3303
- Lacas-Gervais S, 2004, J CELL BIOL, V166, P983, DOI 10.1083/jcb.200408007
- Levy D, 2011, NEURON, V70, P886, DOI 10.1016/j.neuron.2011.05.015
- Li H, 2010, BIOINFORMATICS, V26, P589, DOI 10.1093/bioinformatics/btp698
- Li H, 2009, BIOINFORMATICS, V25, P1754, DOI 10.1093/bioinformatics/btp324
- Lim ET, 2013, NEURON, V77, P235, DOI 10.1016/j.neuron.2012.12.029
- Liu X, 2013, HUM MUTAT
- Maas NMC, 2007, GENET COUNSEL, V18, P357
- Malan V, 2010, EUR J HUM GENET, V18, P227, DOI 10.1038/ejhg.2009.162
- Malhotra D, 2012, CELL, V148, P1223, DOI 10.1016/j.cell.2012.02.039
- Manning M, 2010, GENET MED, V12, P742, DOI 10.1097/GIM.0b013e3181f8baad
- Marshall CR, 2008, AM J HUM GENET, V82, P477, DOI 10.1016/j.ajhg.2007.12.009
- Mau UA, 2000, AM J MED GENET, V91, P180, DOI 10.1002/(SICI)1096-8628(20000320)91:3<180::AID-AJMG4>3.0.CO;2-R
- McKenna A, 2010, GENOME RES, V20, P1297, DOI 10.1101/gr.107524.110
- Miles JH, 2005, AM J MED GENET A, V135A, P171, DOI 10.1002/ajmg.a.30590
- Miles JH, 2008, AM J MED GENET A, V146A, P1101, DOI 10.1002/ajmg.a.32244
- Miller JA, 2014, NATURE, V508, P199, DOI 10.1038/nature13185
- Miosge LA, 2015, P NATL ACAD SCI USA, V112, pE5189, DOI 10.1073/pnas.1511585112
- Moss J, 2009, J INTELL DISABIL RES, V53, P852, DOI 10.1111/j.1365-2788.2009.01197.x
- O'Roak BJ, 2012, SCIENCE, V338, P1619, DOI 10.1126/science.1227764
- O'Roak BJ, 2011, NAT GENET, V43, P585, DOI 10.1038/ng.835
- Orlandini M, 2003, J BIOL CHEM, V278, P44650, DOI 10.1074/jbc.M304255200
- Ou Z, 2011, GENOME RES, V21, P33, DOI 10.1101/gr.111609.110
- Parikshak NN, 2015, NAT REV GENET, V16, P441, DOI 10.1038/nrg3934
- Partington MW, 1997, J MED GENET, V34, P719, DOI 10.1136/jmg.34.9.719
- Pavlopoulos GA, 2011, BIODATA MIN, V4, DOI 10.1186/1756-0381-4-10
- Persico AM, 2013, BEHAV BRAIN RES, V251, P95, DOI 10.1016/j.bbr.2013.06.012
- Pinto D, 2010, NATURE, V466, P368, DOI 10.1038/nature09146
- Purcell S, 2007, AM J HUM GENET, V81, P559, DOI 10.1086/519795
- Ronemus M, 2014, NAT REV GENET, V15, P133, DOI 10.1038/nrg3585
- Samocha KE, 2014, NAT GENET, V46, P944, DOI 10.1038/ng.3050
- Sanders SJ, 2012, NATURE, V485, P237, DOI 10.1038/nature10945
- Sanders SJ, 2011, NEURON, V70, P863, DOI 10.1016/j.neuron.2011.05.002
- Schonewolf-Greulich B, 2013, AM J MED GENET A, V161, P2358, DOI 10.1002/ajmg.a.36099
- Schwartz CM, 2012, J NEUROSCI RES, V90, P1367, DOI 10.1002/jnr.23064
- Sebat J, 2007, SCIENCE, V316, P445, DOI 10.1126/science.1138659
- Shifman S, 2008, PLOS GENET, V4, DOI 10.1371/journal.pgen.0040028
- Skaar DA, 2005, MOL PSYCHIATR, V10, P563, DOI 10.1038/sj.mp.4001614
- Skrlec Ivana, 2014, Coll Antropol, V38, P319
- Smith KR, 2014, NEURON, V84, P399, DOI 10.1016/j.neuron.2014.10.010
- State MW, 2011, NAT NEUROSCI, V14, P1499, DOI 10.1038/nn.2924
- Su L, 2008, NEUROMOL MED, V10, P316, DOI 10.1007/s12017-008-8042-1
- Van der Auwera G. A., 2013, CURR PROTOC BIOINFOR, V11, P1, DOI 10.1002/0471250953.BI1110S43
- Veltman JA, 2012, NAT REV GENET, V13, P565, DOI 10.1038/nrg3241
- Wang J-B, 2013, ELECTRON J DIFFER EQ, V2013, P1, DOI 10.1155/2013/978398
- Wang K, 2010, NUCLEIC ACIDS RES, V38, DOI 10.1093/nar/gkq603
- Welser-Alves JV, 2013, ARTERIOSCL THROM VAS, V33, P943, DOI 10.1161/ATVBAHA.112.300566
- WING L, 1979, J AUTISM DEV DISORD, V9, P11, DOI 10.1007/BF01531288
- Wu JX, 2014, PLOS GENET, V10, DOI 10.1371/journal.pgen.1004237
- Xue-Qi C, 2010, J STAT MECH-THEORY E, V2010
- Yuen Ryan K C, 2015, Nat Med, V21, P185, DOI 10.1038/nm.3792
- Zafeiriou DI, 2013, AM J MED GENET B
- Zhang C, 2014, PROG NEURO-PSYCHOPH, V50, P110, DOI 10.1016/j.pnpbp.2013.12.010