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Translational pediatrics: clinical perspective for Phelan–McDermid syndrome and autism research

Abstract

Phelan–McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease.

Impact

  • Phelan–McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder.

  • Brain organoids are expected to provide therapeutic insight.

  • Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.

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Fig. 1: Clinical relevance of molecular studies and brain organoids from patients with Phelan–McDermid syndrome.
Fig. 2: The interplay between SHANK3 and MECP2-expressing neurons in somatosensory circuits.

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Acknowledgements

We thank the patients and their parents for kindly cooperating with our studies and Kazuaki Nonaka (Professor Emeritus, Kyushu University), Masafumi Sanefuji, Chong Pin Fee, Yuko Ichimiya, Yuri Sonoda, Kousuke Yonemoto, Ryoji Taira, Fumihiko Fujii, and the laboratory members for their helpful discussions.

Funding

This study was supported by JSPS KAKENHI grant numbers JP19K08281, JP18H04042, JP21K10293; AMED under the grant numbers JP20ek0109411 and JP20wm0325002h; a Health and Labour Sciences Research Grant for Prion Diseases under the grant number JP20FC1054; The Japan Epilepsy Research Foundation, and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics. These funders had no role in the design and conduct of the study.

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Y.S. conceptualized the study, drafted the initial manuscript, and revised the manuscript. C.P.S., S. Okuzono, and S. Ohga critically reviewed the intellectual content and revised the manuscript. All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Yasunari Sakai.

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Sakai, Y., Okuzono, S., Schaaf, C.P. et al. Translational pediatrics: clinical perspective for Phelan–McDermid syndrome and autism research. Pediatr Res 92, 373–377 (2022). https://doi.org/10.1038/s41390-021-01806-x

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  • DOI: https://doi.org/10.1038/s41390-021-01806-x

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