Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome

Am J Hum Genet. 2020 Nov 5;107(5):977-988. doi: 10.1016/j.ajhg.2020.09.005. Epub 2020 Oct 14.


PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cβ subunits of PKA during human development.

Keywords: Ellis-van Creveld syndrome; GLI transcritpion factors; PKA; PRKACA; PRKACB; cAMP signaling; congenital heart defects; hedgehog signaling; mosaicism; postaxial polydactyly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adolescent
  • Adult
  • Animals
  • Base Sequence
  • Cognitive Dysfunction / diagnosis
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / pathology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / chemistry
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / deficiency
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
  • Female
  • Fingers / abnormalities*
  • Fingers / pathology
  • Gene Expression Regulation, Developmental
  • Germ-Line Mutation*
  • Heart Septal Defects / diagnosis
  • Heart Septal Defects / genetics*
  • Heart Septal Defects / pathology
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Holoenzymes / chemistry
  • Holoenzymes / deficiency
  • Holoenzymes / genetics
  • Humans
  • Infant, Newborn
  • Male
  • Mice
  • Models, Molecular
  • Mosaicism
  • NIH 3T3 Cells
  • Pedigree
  • Polydactyly / diagnosis
  • Polydactyly / genetics*
  • Polydactyly / pathology
  • Protein Structure, Secondary
  • Toes / abnormalities*
  • Toes / pathology


  • Hedgehog Proteins
  • Holoenzymes
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human
  • PRKACB protein, human

Supplementary concepts

  • Atrioventricular Septal Defect
  • Polydactyly, Postaxial