A recurrent variant in PPP2R5C identified in individuals with macrocephaly, intellectual disability, and seizures

Alison M Muir; Adi Reich; Fanggeng Zou; Deanna Alexis Carere; Sue Moyer Harasink; Lily Tran; Bobbi McGivern

doi:10.1016/j.xhgg.2024.100394

A recurrent variant in PPP2R5C identified in individuals with macrocephaly, intellectual disability, and seizures

HGG Adv. 2024 Dec 17:100394. doi: 10.1016/j.xhgg.2024.100394. Online ahead of print.

Authors

Alison M Muir¹, Adi Reich¹, Fanggeng Zou¹, Deanna Alexis Carere¹, Sue Moyer Harasink², Lily Tran², Bobbi McGivern³

Affiliations

¹ GeneDx, LLC, Gaithersburg MD 20877 USA.
² Nemours Children's Health-Delaware: Division of Neurology, Wilmington, DE, 19803, USA.
³ GeneDx, LLC, Gaithersburg MD 20877 USA. Electronic address: genematcher@genedx.com.

PMID: 39696819
DOI: 10.1016/j.xhgg.2024.100394

Abstract

PPP2R5C encodes a B-type regulatory subunit of protein phosphatase 2A (PP2A). This protein serine/threonine phosphatase is a component of multiple signaling pathways and is an established negative regulator of cell division, growth and proliferation. De novo variants in other subunits of protein phosphatase 2A are associated with neurodevelopment disorders and intellectual disability. We report two unrelated affected individuals with a recurrent variant in PPP2R5C (c.457G>A: p.(Glu153Lys)). Core features in affected individuals include macrocephaly, intellectual disability, hypotonia, and seizures. The Glu153 residue is part of a highly conserved acidic loop and directly interacts with the PP2A catalytic subunit. Our results support heterozygous PPP2R5C missense variants as a potential cause of macrocephaly and neurodevelopmental disorder.