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De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

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Abstract

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

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Acknowledgments

We thank the patients and their families for their generous participation. This work was supported in part by a grant from the Simons Foundation and from the NIH (GM030518), NINDS (NS058529), and NHGRI/NHLBI (HG006542).

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Authors and Affiliations

  1. Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA

    Lijiang Ma & Wendy K. Chung

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Yavuz Bayram, Yunru Shao, Daryl A. Scott, Andrea M. Lewis, Janson J. White, Shalani N. Jhangiani, Seema R. Lalani & James R. Lupski

  3. GeneDx, Gaithersburg, MD, USA

    Heather M. McLaughlin, Megan T. Cho, Kyle Retterer, Rhonda E. Schnur, Ingrid M. Wentzensen & Sherri Bale

  4. Walter Reed National Military Medical Center, Bethesda, MD, USA

    Alyson Krokosky & Clesson E. Turner

  5. Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ, USA

    Kristin Lindstrom

  6. Spectrum Health, Grand Rapids, MI, USA

    Caleb P. Bupp & Katey Mayberry

  7. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    Weiyi Mu & Joann Bodurtha

  8. Division of Genetics and Metabolism, Children’s National Medical Center, Washington, DC, USA

    Veronique Weinstein

  9. Genetics Center, Orange, CA, USA

    Neda Zadeh

  10. Ambry Genetics, Aliso Viejo, CA, USA

    Wendy Alcaraz & Zöe Powis

  11. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

    Daryl A. Scott

  12. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Shalani N. Jhangiani & James R. Lupski

  13. Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

    Elif Yilmaz Gulec

  14. Texas Children’s Hospital, Houston, TX, USA

    James R. Lupski

  15. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    James R. Lupski

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  1. Lijiang Ma
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Correspondence to Wendy K. Chung.

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Conflict of interest

Heather McLaughlin, Megan Cho, Kyle Retterer, Rhonda Schnur, Ingrid Wentzensen, and Sherri Bale are employees of GeneDx. Wendy Chung is a former employee of GeneDx and a paid consultant for Regeneron Pharmaceuticals. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., serves on the Scientific Advisory Board of the Baylor Miraca Genetics Laboratory, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The other authors declare that they have no conflict of interest.

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Ma, L., Bayram, Y., McLaughlin, H.M. et al. De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease. Hum Genet 135, 1399–1409 (2016). https://doi.org/10.1007/s00439-016-1731-1

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