De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease.
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.
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
Lijiang
L
Ma
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Yavuz
Y
Bayram
GeneDx, Gaithersburg, MD, USA.
Heather M
HM
McLaughlin
GeneDx, Gaithersburg, MD, USA.
Megan T
MT
Cho
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Alyson
A
Krokosky
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Clesson E
CE
Turner
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.
Kristin
K
Lindstrom
Spectrum Health, Grand Rapids, MI, USA.
Caleb P
CP
Bupp
Spectrum Health, Grand Rapids, MI, USA.
Katey
K
Mayberry
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Weiyi
W
Mu
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Joann
J
Bodurtha
Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
Veronique
V
Weinstein
Genetics Center, Orange, CA, USA.
Neda
N
Zadeh
Ambry Genetics, Aliso Viejo, CA, USA.
Wendy
W
Alcaraz
Ambry Genetics, Aliso Viejo, CA, USA.
Zöe
Z
Powis
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Yunru
Y
Shao
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
Daryl A
DA
Scott
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Andrea M
AM
Lewis
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Janson J
JJ
White
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Shalani N
SN
Jhangiani
Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
Elif Yilmaz
EY
Gulec
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Seema R
SR
Lalani
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.|Texas Children's Hospital, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
James R
JR
Lupski
GeneDx, Gaithersburg, MD, USA.
Kyle
K
Retterer
GeneDx, Gaithersburg, MD, USA.
Rhonda E
RE
Schnur
GeneDx, Gaithersburg, MD, USA.
Ingrid M
IM
Wentzensen
GeneDx, Gaithersburg, MD, USA.
Sherri
S
Bale
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA. wkc15@columbia.edu.
Wendy K
WK
Chung
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000235:genetics*
C517188:PPP1CB protein, human; D054645:Protein Phosphatase 1
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