A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes

Abstract

Rare genetic disorders represent some of the most severe and life-limiting conditions that constitute a considerable burden on global healthcare systems and societies. Most individuals affected by rare disorders remain undiagnosed, highlighting the unmet need for improved disease gene discovery and novel variant interpretation. Aberrant (de) phosphorylation can have profound pathological consequences underpinning many disease processes. Numerous phosphatases and associated proteins have been identified as disease genes, with many more likely to have gone undiscovered thus far. To begin to address these issues, we have performed a systematic survey of de novo variants amongst 189 genes encoding phosphatase catalytic subunits found in rare disease patients recruited to the 100,000 Genomes Project (100 kGP), the largest national sequencing project of its kind in the United Kingdom. We found that 49% of phosphatases were found to carry de novo mutation(s) in this cohort. Only 25% of these phosphatases have been previously linked to genetic disorders. A gene-to-patient approach matching variants to phenotypic data identified 9 novel candidate rare-disease genes: PTPRD, PTPRG, PTPRT, PTPRU, PTPRZ1, MTMR3, GAK, TPTE2, PTPN18. As the number of patients undergoing whole genome sequencing increases and information sharing improves, we anticipate that reiterative analysis of genomic and phenotypic data will continue to identify candidate phosphatase disease genes for functional validation. This is the first step towards delineating the aetiology of rare genetic disorders associated with altered phosphatase function, leading to new biological insights and improved clinical outcomes for the affected individuals and their families.

Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex

“…Interestingly, neurodevelopmental disorders related to increased cortical neurons are often associated with impaired neuronal phenotypes and behavioral alterations ( Fang et al, 2014 ). Regarding the role of PTPRD in neurogenesis, our observations align with this hypothesis since previous studies have found that PTPRD KO mice have aberrant dendritic processes ( Nakamura et al, 2017 ), impaired synaptic development and function ( Takahashi et al, 2012 ; Park et al, 2020 ; Sclip and Südhof, 2020 ), and behavioral deficits ( Drgonova et al, 2015 ; Uhl et al, 2018 ; Park et al, 2020 ; Ho et al, 2023 ), which could explain the contribution of PTRPD mutations to neurodevelopmental disorders ( Schormair et al, 2008 ; Elia et al, 2010 ; Pinto et al, 2010 ; Levy et al, 2011 ; Yang et al, 2011 ; Gai et al, 2012 ; Gazzellone et al, 2016 ; Liu et al, 2016 ; Li et al, 2018 ; Li et al, 2023 ; Lyulcheva-Bennett and Bennett, 2023 ).…”