Verbinnen et al., 2025 described a cohort of 26 individuals with predominantly de novo missense variants in the PPP2R5C gene who presented with a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum characterized by neurodevelopmental delay and hypotonia with a high risk of epilepsy, behavioral problems, macrocephaly, and mildly dysmorphic facial features; 5 individuals in this cohort were reported to have been diagnosed with autism spectrum disorder. Additional biochemical assessment of PPP2R5C variants reported in Verbinnen et al., 2025 demonstrated defects in subunit binding, substrate binding, and/or phosphatase catalytic activity. Muir et al., 2024 had previously reported a recurrent missense variant in PPP2R5C (NM_001161725.2:c.457G>A;p.Glu153Lys) in five unrelated individuals with overlapping clinical features of macrocephaly, intellectual disability, and seizures; detailed clinical summaries of two of the five individuals with this recurrent missense variant reported one individual with autism spectrum disorder. De novo missense variants in PPP2R5C that were predicted to be damaging (CADD > 25) were also reported in an ASD proband from the SAGE cohort (Guo et al., 2019) and in a male ASD proband from the SPARK cohort (Feliciano et al., 2019). Association analysis of ASD families from the Autism Genome Project (AGP) Consortium in Anney et al., 2010 identified an intronic SNP in the PPP2R5C gene (rs7142002) as fulfilling the threshold for association with ASD (P < 5.0E-06).
Molecular Function
The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a gamma isoform of the regulatory subunit B56 subfamily.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum
