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Hum Genet. 2016 Dec;135(12):1399-1409. Epub 2016 Sep 28.

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

Author information

1
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
3
GeneDx, Gaithersburg, MD, USA.
4
Walter Reed National Military Medical Center, Bethesda, MD, USA.
5
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.
6
Spectrum Health, Grand Rapids, MI, USA.
7
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
8
Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
9
Genetics Center, Orange, CA, USA.
10
Ambry Genetics, Aliso Viejo, CA, USA.
11
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
12
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
13
Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
14
Texas Children's Hospital, Houston, TX, USA.
15
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
16
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA. wkc15@columbia.edu.

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.

PMID:
27681385
PMCID:
PMC5663278
DOI:
10.1007/s00439-016-1731-1
[Indexed for MEDLINE]
Free PMC Article

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