title: Whole-genome sequencing in an autism multiplex family.
abstract: BACKGROUND
  Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism.
  
  
  METHODS
  To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes.
  
  
  RESULTS
  By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies.
  
  
  CONCLUSIONS
  Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases.
authors.affiliation: Department of Psychiatry, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Shi
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510641, China.|BGI Tianjin, Tianjin 300308, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Golhar
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Otieno
authors.affiliation: BGI Tianjin, Tianjin 300308, China.
authors.forename: Mingze
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, New York, NY 11724, USA.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
authors.affiliation: Department of Psychiatry, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.|Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson