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Original research
Genotype and phenotype correlation of PHACTR1-related neurological disorders
  1. Zhao Xu1,2,
  2. Lynette Sadleir3,
  3. Himanshu Goel4,
  4. Xianru Jiao1,2,
  5. Yue Niu1,2,
  6. Zongpu Zhou1,2,
  7. Guillem de Valles-Ibáñez3,
  8. Gemma Poke3,
  9. Michael Hildebrand5,6,
  10. Nico Lieffering3,
  11. Jiong Qin1,2,
  12. Zhixian Yang1,2
  1. 1 Department of Pediatrics, Peking University People's Hospital, Beijing, China
  2. 2 Epilepsy Center, Peking University People's Hospital, Beijing, China
  3. 3 Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand
  4. 4 Hunter Genetics, Waratah, New South Wales, Australia
  5. 5 Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia
  6. 6 Neuroscience Research Group, Murdoch Children’s Research Institute, Royal Children's Hospital, South Brisbane, Queensland, Australia
  1. Correspondence to Dr Zhixian Yang, Department of Pediatrics, Peking University People's Hospital, Beijing 100044, China; zhixian.yang{at}


Background PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein–protein interaction.

Methods We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype–phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein–protein interactions and interfaces.

Results Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1–PPP1CA or PHACTR1–G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain).

Conclusions Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.

  • Epilepsy
  • Genetics, Medical
  • Genotype
  • Neurology
  • Pediatrics

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Contributors ZY and ZX planned and designed the study. ZX, LS, HG, XJ, YN, ZZ, GdV-I, GP, MH, NL and JQ collected and reported clinical data. ZX, LS and HG analysed the clinical data. ZX conducted protein structure-related studies. ZY was responsible for overseeing data collection and analysis. ZX drafted the manuscript under the supervision of ZY. LS and HG revised the manuscript. All authors participated in the revision and approval of the final manuscript. ZY is responsible for the overall content and acts as guarantor.

  • Funding This work was supported by the National Natural Science Foundation of China (grant: 82171436); Beijing Health Promotion Research Fund Project (2020-2-4077); 2018 Beijing Clinical Key Specialty Construction Project-Pediatrics Foundation (2199000726); People’s Hospital School Construction Project (BMU2023XY016); Peking University People’s Hospital Talent Introduction Start-up Fund (2023-T-02) and Peking University People’s Hospital R&D Fund Unveiling Project (RDGS2023-10).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.