Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder

PLoS One. 2015 Feb 3;10(2):e0116358. doi: 10.1371/journal.pone.0116358. eCollection 2015.


Introduction: Clinical genomics promise to be especially suitable for the study of etiologically heterogeneous conditions such as Autism Spectrum Disorder (ASD). Here we present three siblings with ASD where we evaluated the usefulness of Whole Genome Sequencing (WGS) for the diagnostic approach to ASD.

Methods: We identified a family segregating ASD in three siblings with an unidentified cause. We performed WGS in the three probands and used a state-of-the-art comprehensive bioinformatic analysis pipeline and prioritized the identified variants located in genes likely to be related to ASD. We validated the finding by Sanger sequencing in the probands and their parents.

Results: Three male siblings presented a syndrome characterized by severe intellectual disability, absence of language, autism spectrum symptoms and epilepsy with negative family history for mental retardation, language disorders, ASD or other psychiatric disorders. We found germline mosaicism for a heterozygous deletion of a cytosine in the exon 21 of the SHANK3 gene, resulting in a missense sequence of 5 codons followed by a premature stop codon (NM_033517:c.3259_3259delC, p.Ser1088Profs*6).

Conclusions: We reported an infrequent form of familial ASD where WGS proved useful in the clinic. We identified a mutation in SHANK3 that underscores its relevance in Autism Spectrum Disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Mutational Analysis*
  • Female
  • Genomics*
  • Humans
  • Male
  • Mosaicism
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Pedigree*
  • Siblings


  • Nerve Tissue Proteins
  • SHANK3 protein, human

Grant support

This work was supported by an unrestricted grant from the Ministry of Science and Technology of the government of Argentina. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.