Lyulcheva-Bennett, Ekaterina 
ORCID: 0000-0002-2472-5829 and Bennett, Daimark
(2023)
A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 11.
1107930-.
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 <i>de novo</i> 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 <i>de novo</i> 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | de novo mutation, developmental disorder, disease genes, genome sequencing, mendelian disease, phosphatase, phosphatome, rare disorders |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 14 Dec 2023 08:47 |
| Last Modified: | 14 Dec 2023 08:48 |
| DOI: | 10.3389/fcell.2023.1107930 |
| Open Access URL: | https://doi.org/10.3389/fcell.2023.1107930 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177358 |
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