Human Genetics

, Volume 134, Issue 10, pp 1055–1068 | Cite as

Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes

  • Nicola H. Chapman
  • Alejandro Q. NatoJr.
  • Raphael Bernier
  • Katy Ankenman
  • Harkirat Sohi
  • Jeff Munson
  • Ashok Patowary
  • Marilyn Archer
  • Elizabeth M. Blue
  • Sara Jane Webb
  • Hilary Coon
  • Wendy H. Raskind
  • Zoran Brkanac
  • Ellen M. Wijsman
Original Investigation


Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12–47 individuals), each with ≥3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.


Autism Spectrum Disorder Whole Exome Sequencing Broad Autism Phenotype Unaffected Individual Sort Intolerant From Tolerant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Autism spectrum disorder


Whole exome sequencing


Autism Diagnostic Observational Schedule


Autism Diagnostic Interview – Revised


Broader Phenotype Autism Symptom Scale


Broader autism phenotype


Illumina HumanOmniExpress


Illumina Human Core Exome


1,000 genome project Europeans


Inheritance vectors


Markov chain Monte Carlo



Research reported in this publication was supported by funding from the National Institute of Mental Health, and the National Institute on Aging, under award numbers R01MH092367, R01MH094293, R01MH094400, and R00AG040184 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We would like to thank those with ASD and their families, because without their participation this research would not be possible.

Ethical approval

“All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”

Supplementary material

439_2015_1585_MOESM1_ESM.pdf (60 kb)
Supplementary material 1 (PDF 61 kb)
439_2015_1585_MOESM2_ESM.pdf (180 kb)
Supplementary material 2 (PDF 181 kb)
439_2015_1585_MOESM3_ESM.pdf (107 kb)
Supplementary material 3 (PDF 107 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Nicola H. Chapman
    • 1
  • Alejandro Q. NatoJr.
    • 1
  • Raphael Bernier
    • 2
  • Katy Ankenman
    • 9
  • Harkirat Sohi
    • 1
  • Jeff Munson
    • 2
    • 3
  • Ashok Patowary
    • 2
  • Marilyn Archer
    • 2
  • Elizabeth M. Blue
    • 1
  • Sara Jane Webb
    • 2
    • 3
  • Hilary Coon
    • 4
    • 5
  • Wendy H. Raskind
    • 1
    • 2
    • 7
  • Zoran Brkanac
    • 2
  • Ellen M. Wijsman
    • 1
    • 6
    • 7
    • 8
  1. 1.Division of Medical Genetics, School of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  3. 3.Center on Child Development and DisabilityUniversity of WashingtonSeattleUSA
  4. 4.Department of Internal MedicineUniversity of UtahSalt Lake CityUSA
  5. 5.Department of Psychiatry, School of MedicineUniversity of UtahSalt Lake CityUSA
  6. 6.Department of BiostatisticsUniversity of WashingtonSeattleUSA
  7. 7.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  8. 8.University of WashingtonSeattleUSA
  9. 9.Department of PsychiatryUniversity of CaliforniaSan FranciscoUSA

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