De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Abstract

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

A snapshot of some pLI score pitfalls

“…On the contrary, the residual truncated protein may behave like a gain‐in‐function mutant. This is, for example, the case of PPM1D, a gene responsible for severe intellectual disability (Jansen et al, ), for which the pLI score is close to nil because de novo PTVs are all located in the last or penultimate exons. Such variants in genes truly intolerant to loss‐of‐function may also be present in control databases and contribute to a decrease in the pLI scores of the genes concerned.…”

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

“…For example, there are 14 genes significant for LGD recurrence with a pLI below 0.9 and RVIS percentile above 20 and these would be predicted to be enriched for false disease associations 43 . However, half (7/14) of these genes have an established association with ASD or ID/DD, including four X chromosome-linked genes (MECP2, ZC4H2, UPF3B, HDAC8) [44][45][46][47] and three autosomal genes (ASXL1, PURA, PPM1D) [48][49][50] . The remaining seven genes lack support in the literature (ENO3, HIVEP3, C9orf142, KCNS3, NFE2L3, SALL3, GPRIN1) strongly linking them to ID/DD or ASD.…”

PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

“…To examine if mutations are present in neuroblastoma, we next performed whole exome sequencing (WES) or whole genome sequencing (WGS) of neuroblastoma patient samples to screen for germline and somatic mutations. Notably, we identified a pathogenic truncating previously not been reported in cancer but have been observed in children with intellectual disabilities and neurodevelopmental disorders 24,25 . Both these neuroblastoma-associated PPM1D mutations predictably give rise to C-terminal truncated variants of WIP1 similar to those described in other cancers ( Figure 1E) (http//:www.cancer.sanger.ac.uk/cosmic/ mutation/).…”