PPP2R1A neurodevelopmental disorder is associated with congenital heart defects.

Creator(s)

Elizabeth K. Baker
Beulah Solivio
Ben Pode-Shakked
Laura A. Cross, Children's Mercy HospitalFollow
Bonnie Sullivan, Children's Mercy HospitalFollow
Annick Raas-Rothschild
Odelia Chorin
Ortal Barel
Omer Bar-Yosef
Ammar Husami
Robert J. Hopkin
Carlos E. Prada
Rolf W. Stottmann
Kathryn Nicole Weaver

Document Type

Article

Publication Date

11-2022

Identifier

DOI: 10.1002/ajmg.a.62946

Abstract

Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding "Aα" subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous PPP2R1A variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548G>A, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544C>T, p.R182W) and presented with agenesis of corpus callosum, ventriculomegaly, mild pulmonic stenosis, and small patent foramen ovale. Individual 4 has a novel variant (c.536C>A, p.P179H), ventriculomegaly, and atrial septal defect. To conclude, we propose expansion of the phenotype of PPP2R1A neurodevelopmental disorder to include CHD. Further, the R183Q variant has now been described in three individuals, all with severe neurologic abnormalities, severe CHD, and early death suggesting that this variant may be particularly deleterious.

Journal Title

American journal of medical genetics. Part A

Volume

188

Issue

11

First Page

3262

Last Page

3277

MeSH Keywords

Heart Defects, Congenital; Humans; Hydrocephalus; Nervous System Malformations; Neurodevelopmental Disorders; Protein Phosphatase 2; Serine; Transcription Factors

Keywords

PPP2R1A; congenital heart defects; neurodevelopmental disorder; protein phosphatase 2A

Recommended Citation

Baker EK, Solivio B, Pode-Shakked B, et al. PPP2R1A neurodevelopmental disorder is associated with congenital heart defects. Am J Med Genet A. 2022;188(11):3262-3277. doi:10.1002/ajmg.a.62946