Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder

PLoS One. 2017 Jan 24;12(1):e0170386. doi: 10.1371/journal.pone.0170386. eCollection 2017.


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.

Publication types

  • Case Reports

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Child
  • Chromosomes, Human, Pair 4 / genetics*
  • Chromosomes, Human, Pair 4 / ultrastructure
  • Chromosomes, Human, Pair 8 / genetics*
  • Chromosomes, Human, Pair 8 / ultrastructure
  • Comparative Genomic Hybridization*
  • DNA Copy Number Variations*
  • Exome / genetics*
  • Female
  • Gene Duplication
  • Gene Regulatory Networks
  • Genetic Association Studies*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intellectual Disability / genetics
  • Learning Disabilities / genetics
  • Male
  • Megalencephaly / genetics
  • Nerve Tissue Proteins / genetics
  • Nucleic Acid Amplification Techniques
  • Sequence Deletion
  • Siblings
  • Syndrome
  • Translocation, Genetic*


  • Nerve Tissue Proteins

Grant support

This work was supported by grants from: FAPESP – São Paulo Research Foundation (, grant number 2011/04956-6 received by HB and also grant number 2011/14658-2 received by VNSR (scholarship); CAPES – Brazilian Federal Agency for the Support and Evaluation of Graduate Education (PROEX-33002010073P7), received by VNSR (scholarship). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.