title: Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder.
abstract: 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-single nucleotide variants (SNVs) or small insertions and deletions (indels)-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.
authors.affiliation: LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Viviane Neri de Souza
authors.identifier: http://orcid.org/0000-0002-4959-2954
authors.initials: VN
authors.lastname: Reis
authors.affiliation: Bioinformatics, Mendelics Análise Genômica, São Paulo, Brazil.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Kitajima
authors.affiliation: LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Tahira
authors.affiliation: LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Ana Cecília
authors.initials: AC
authors.lastname: Feio-Dos-Santos
authors.affiliation: Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo Ambrósio
authors.initials: RA
authors.lastname: Fock
authors.affiliation: LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Bianca Cristina Garcia
authors.initials: BC
authors.lastname: Lisboa
authors.affiliation: Department of Informatics, Federal Institute of Espírito Santo, Serra, Brazil.
authors.forename: Sérgio Nery
authors.initials: SN
authors.lastname: Simões
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Ana C V
authors.initials: AC
authors.lastname: Krepischi
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Naila Cristina
authors.initials: NC
authors.lastname: Lourenço
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.affiliation: LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002648:Child; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000648:ultrastructure; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics; D007859:Learning Disabilities / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D021141:Nucleic Acid Amplification Techniques; D017384:Sequence Deletion; D035781:Siblings; D013577:Syndrome; D014178:Translocation, Genetic
chemical_list: D009419:Nerve Tissue Proteins