PPP2R5D – Syndromic Intellectual Disability with Overgrowth

PPP2R5D encodes the B56δ regulatory subunit of protein phosphatase 2A, and heterozygous variants in this gene underlie a syndromic intellectual disability characterized by macrocephaly and overgrowth ([HP:0001548]). The association between PPP2R5D and syndromic ID with overgrowth has been established through multiple independent cohorts and robust functional studies.

Genetic analyses across over 100 unrelated individuals have identified predominantly de novo missense variants in PPP2R5D, including recurrent hotspots such as c.1258G>A (p.Glu420Lys). In a large international series of 76 affected individuals, 68 harbored pathogenic de novo variants, confirming autosomal dominant inheritance and satisfying de novo criteria ([PMID:36216457]).

Segregation studies include both sporadic and familial cases. A multigenerational Chinese pedigree demonstrated cosegregation of a novel nonsense mutation c.1321C>T (p.Arg441Ter) with disease in two affected relatives, while one carrier remained unaffected, indicating incomplete penetrance ([PMID:36403339]). Overall, two additional affected relatives were reported segregating PPP2R5D variants.

Functional characterization in cellular models confirms a dominant‐negative mechanism. CRISPR‐edited HEK293 lines bearing E420K or E198K variants show constitutive AKT-mTORC1 activation, RPS6 hyperphosphorylation, and increased cell size, all reversible by rapamycin or p70S6K inhibition ([PMID:33482199], [PMID:38150499]). Biochemical assays reveal impaired PP2A holoenzyme assembly and altered substrate binding consistent with pathogenic disruption of phosphatase regulation.

Despite the overall concordance, a single familial case shows incomplete penetrance, underscoring variable expressivity. No studies have refuted the core association or implicated alternate mechanisms in overgrowth syndromes.

In summary, PPP2R5D demonstrates definitive clinical validity for autosomal dominant syndromic intellectual disability with overgrowth. Genetic and functional evidence converge on a dominant‐negative mechanism compromising PP2A regulation. PPP2R5D sequencing has high diagnostic yield in overgrowth with ID and informs therapeutic strategies targeting mTORC1.

Key Take-home: PPP2R5D variants cause a dominantly inherited overgrowth syndrome with intellectual disability, and targeted mTOR inhibition may offer clinical benefit.

References

• American journal of medical genetics. Part A • 2021 • Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India. PMID:33942996
• Clinical neurology and neurosurgery • 2022 • A novel nonsense mutation in PPP2R5D is associated with neurodevelopmental disorders and shows incomplete penetrance in a Chinese pedigree. PMID:36403339
• Journal of medical genetics • 2023 • Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype-phenotype analysis. PMID:36216457
• The Journal of Biological Chemistry • 2021 • A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth. PMID:33482199
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations PMID:38150499

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