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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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).
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
- Congenital Heart Disease
- Intellectual Disability
- Intellectual Disability
- Okadaic Acid
- Missense Variant