The PPM1D gene encodes a member of the PP2C family of serine/threonine protein phosphatases which are negative regulators of cell stress response pathways. Association between PPM1D variants and autosomal dominant syndromic intellectual disability (Jansen-de Vries syndrome) was first reported in 2017 (Jansen et al., PMID: 28343630). Since then, at least 20 truncating variants, most of which are de novo, have been reported in individuals with intellectual disability and/or developmental delay, hypotonia, behavioral problems including autism spectrum disorder, high pain threshold, and facial dysmorphism (PMIDs: 28343630, 29758292, 30795918, 30979967, 31916397, 32399599). All the variants are located in the last or penultimate exon and are expected to escape nonsense-mediated mRNA decay, which is supported by the presence of truncated PPM1D transcripts in patient-derived cells (PMID: 28343630). In addition, these cells showed a cell-growth disadvantage after exposure to ionizing radiation, suggesting a possible effect on the stress-response pathway (PMID: 28343630).
PPM1D has a pLI of 0 in gnomAD (v2.1.1), with 49 observed truncating variants. Mosaic C-terminal truncating PPM1D variants in blood are associated with clonal hematopoiesis during aging and cancer therapy (PMID: 34963005). This suggests that some of the truncating variants in gnomAD, many of which exhibit allelic imbalance, may represent somatic mosaicism.
In summary, PPM1D is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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