title: Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.
abstract: BACKGROUND
  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.
authors: Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina.
authors: Sergio I
authors: SI
authors: Nemirovsky
authors: Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
authors: Marta
authors: M
authors: Córdoba
authors: Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina.
authors: Jonathan J
authors: JJ
authors: Zaiat
authors: Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina.
authors: Sabrina P
authors: SP
authors: Completa
authors: Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
authors: Patricia A
authors: PA
authors: Vega
authors: Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
authors: Dolores
authors: D
authors: González-Morón
authors: Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
authors: Nancy M
authors: NM
authors: Medina
authors: Instituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Predio CCT, Rosario, Argentina.
authors: Mónica
authors: M
authors: Fabbro
authors: Instituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Predio CCT, Rosario, Argentina.
authors: Soledad
authors: S
authors: Romero
authors: Instituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Predio CCT, Rosario, Argentina.
authors: Bianca
authors: B
authors: Brun
authors: Instituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Predio CCT, Rosario, Argentina.
authors: Santiago
authors: S
authors: Revale
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: María Florencia
authors: MF
authors: Ogara
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Adali
authors: A
authors: Pecci
authors: Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina; Departamento de Química Biológica, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, INQUIMAE/CONICET, Buenos Aires, Argentina.
authors: Marcelo
authors: M
authors: Marti
authors: Instituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Predio CCT, Rosario, Argentina.
authors: Martin
authors: M
authors: Vazquez
authors: Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina; Departamento de Química Biológica, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, INQUIMAE/CONICET, Buenos Aires, Argentina.
authors: Adrián
authors: A
authors: Turjanski
authors: Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
authors: Marcelo A
authors: MA
authors: Kauffman
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D035781:Siblings
chemical_list: D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human
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