Integrative variation analysis reveals that a complex genotype may specify phenotype in siblings with syndromic autism spectrum disorder

Viviane Neri De Souza Reis, João Paulo Kitajima, Ana Carolina Tahira, Ana Cecília Feio-Dos-santos, Rodrigo Ambró Sio Fock, Bianca Cristina Garcia Lisboa, Sérgio Nery Simões, Ana C.V. Krepischi, Carla Rosenberg, Naila Cristina Lourenço, Maria Rita Passos-Bueno, Helena Brentani

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Article numbere0170386
    JournalPloS one
    Volume12
    Issue number1
    DOIs
    StatePublished - Jan 2017

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

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