PPP2R1A neurodevelopmental disorder is associated with congenital heart defects

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• Protein Phosphatase 2A (PP2A) is a crucial serine/threonine phosphatase regulating diverse biological functions.
• PPP2R1A encodes the scaffolding Aα subunit of PP2A, and its pathogenic variants are associated with neurodevelopmental disorders.
• Congenital heart defects (CHD) have been rarely reported in patients with PPP2R1A variants.

Purpose of the Study:

• To report new individuals with pathogenic PPP2R1A variants and congenital heart defects (CHD).
• To investigate the structural mechanisms underlying phenotype variability in PPP2R1A-associated disorders.
• To propose an expansion of the clinical phenotype associated with PPP2R1A variants.

Main Methods:

• Clinical evaluation of four unrelated individuals with pathogenic heterozygous PPP2R1A variants.
• Analysis of patient phenotypes, including neurodevelopmental abnormalities and congenital heart defects.
• Modeling of crystal structures for several PPP2R1A variants to understand their functional impact.

Main Results:

• Four new individuals with pathogenic PPP2R1A variants and varying degrees of CHD were identified.
• Specific variants (R183Q, R182W, P179H) were associated with phenotypes including ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and diverse CHDs.
• The R183Q variant was observed in three individuals with severe neurologic issues, severe CHD, and early mortality, suggesting a particularly detrimental effect.

Conclusions:

• Congenital heart defects (CHD) should be considered part of the expanded phenotype of PPP2R1A-related neurodevelopmental disorder.
• Structural modeling provides insights into the mechanisms of phenotype disparity caused by different PPP2R1A variants.
• The PPP2R1A R183Q variant appears to be associated with a particularly severe and often lethal phenotype.