title: De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.
abstract: Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Linshan
authors.initials: L
authors.lastname: Shang
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Henderson
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Petrey
authors.affiliation: University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Chin-To
authors.initials: CT
authors.lastname: Fong
authors.affiliation: University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Haude
authors.affiliation: Albany Medical Center, Albany, NY, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Shur
authors.affiliation: Albany Medical Center, Albany, NY, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Lundberg
authors.affiliation: Valley Children's Hospital, Madera, CA, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hauser
authors.affiliation: Valley Children's Hospital, Madera, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Carmichael
authors.affiliation: Division of Pediatric Genetics, University of Michigan Health System, Ann Arbor, MI, USA.|Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Innis
authors.affiliation: Division of Pediatric Genetics, University of Michigan Health System, Ann Arbor, MI, USA.|Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Schuette
authors.affiliation: Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Yvonne W
authors.initials: YW
authors.lastname: Wu
authors.affiliation: Child and Adolescent Neurology Consultants, Sacramento, CA, USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Asaikar
authors.affiliation: District Medical Group, Scottsdale, AZ, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Pearson
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Leandra
authors.initials: L
authors.lastname: Folk
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.|Department of Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000453:epidemiology / Q000235:genetics; D001321:Autistic Disorder / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000453:epidemiology / Q000235:genetics*; D009123:Muscle Hypotonia / Q000453:epidemiology / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D054648:Protein Phosphatase 2 / Q000235:genetics*
chemical_list: C525691:PPP2R5D protein, human; D054648:Protein Phosphatase 2
keywords: Autism spectrum disorder; De novo mutations; Intellectual disabilities; PPP2R5D; Protein phosphatase; Whole-exome sequencing