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Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness

Molecular Psychiatry volume 21, pages 1690–1695 (2016)Cite this article

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Abstract

A current focus in psychiatric genetics is detection of multiple common risk alleles through very large genome-wide association study analyses. Yet families do exist, albeit rare, that have multiple affected members who are presumed to have a similar inherited cause to their illnesses. We hypothesized that within some of these families there may be rare highly penetrant mutations that segregate with illness. In this exploratory study, the genomes of 90 individuals across nine families were sequenced. Each family included a minimum of three available relatives affected with a psychotic illness and three available unaffected relatives. Twenty-six variants were identified that are private to a family, alter protein sequence, and are transmitted to all sequenced affected individuals within the family. In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. This variant lies within the consensus SH3 protein-binding motif by which SHANK2 may interact with post-synaptic glutamate receptors. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome. Both variants represent candidates that may be causal for psychotic disorders when considered in the context of their transmission pattern and known gene and disease biology.

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Acknowledgements

The pedigree collections were partially supported by NIMH from 1992–1999 (MHR01 44245) and more recently by Amgen 2013-present. We acknowledge the patients and families who contributed samples and made this study possible.

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Authors and Affiliations

  1. Amgen, Genome Analysis Unit, South San Francisco, CA, USA

    O R Homann, K Misura & S I McDonough

  2. Amgen, Genome Analysis Unit, Thousand Oaks, CA, USA

    E Lamas & R W Sandrock

  3. The BVARI Foundation, VA Boston Healthcare System, Boston, MA, USA

    P Nelson & L E DeLisi

  4. VA Boston Healthcare System, Boston, MA, USA

    L E DeLisi

  5. Department of Psychiatry, Harvard Medical School, Brockton, MA, USA

    L E DeLisi

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  1. O R Homann
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  2. K Misura
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  3. E Lamas
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Correspondence to L E DeLisi.

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Competing interests

LED has received funds from Amgen for clinical evaluations of multiplex families. All other co-authors are employees of Amgen. The company, however, did not influence the study design, analyses or interpretation of the results presented in this manuscript.

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Homann, O., Misura, K., Lamas, E. et al. Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness. Mol Psychiatry 21, 1690–1695 (2016). https://doi.org/10.1038/mp.2016.24

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