A recurrent variant in PPP2R5C identified in individuals with macrocephaly, intellectual disability, and seizures
Alison M Muir1, Adi Reich1, Fanggeng Zou1
1GeneDx, LLC, Gaithersburg, MD 20877, USA.
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 PP2A are associated with neurodevelopment disorders and intellectual disability (ID). We report two unrelated affected individuals with a recurrent variant in PPP2R5C (c.457G>A: p.(Glu153Lys)). Core features in affected individuals include macrocephaly, ID, 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.
Insights
Genetic variants in PPP2R5C can cause neurodevelopmental disorders. This study identifies a recurrent PPP2R5C variant linked to macrocephaly, intellectual disability, and seizures in affected individuals.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Protein phosphatase 2A (PP2A) is crucial in cell signaling and regulation.
- Variants in PP2A subunits are linked to neurodevelopmental disorders and intellectual disability (ID).
Purpose of the Study:
- To investigate the role of PPP2R5C variants in neurodevelopmental disorders.
- To report a recurrent variant in PPP2R5C associated with specific clinical features.
Main Methods:
- Analysis of genetic variants in affected individuals.
- Clinical assessment of core features including macrocephaly, ID, hypotonia, and seizures.
- Structural analysis of the identified variant's impact on PP2A function.
Main Results:
- Two unrelated individuals presented with a recurrent heterozygous missense variant (c.457G>A: p.(Glu153Lys)) in PPP2R5C.
- Core clinical features included macrocephaly, intellectual disability (ID), hypotonia, and seizures.
- The Glu153Lys substitution affects a conserved residue critical for PP2A catalytic subunit interaction.
Conclusions:
- Heterozygous missense variants in PPP2R5C are implicated as a cause of macrocephaly and neurodevelopmental disorders.
- This finding expands the understanding of PP2A subunit involvement in human neurodevelopment.
- PPP2R5C should be considered in the genetic diagnosis of individuals with unexplained macrocephaly and neurodevelopmental conditions.
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