@article{06168924027140f7b8fa4190b769777a,
title = "Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome",
abstract = "Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.",
keywords = "Autism, Intellectual disability, Neurodevelopment, PLXNA3, Plexin, Semaphorin",
author = "Steele, {Jacqueline L.} and Morrow, {Michelle M.} and Sarnat, {Harvey B.} and Ebba Alkhunaizi and Tracy Brandt and Chitayat, {David A.} and DeFilippo, {Colette P.} and Douglas, {Ganka V.} and Dubbs, {Holly A.} and Elloumi, {Houda Zghal} and Glassford, {Megan R.} and Hannibal, {Mark C.} and H{\'e}ron, {B. n{\'e}dicte} and Kim, {Linda E.} and Marco, {Elysa J.} and Cyril Mignot and Monaghan, {Kristin G.} and Myers, {Kenneth A.} and Sumit Parikh and Quinonez, {Shane C.} and Farrah Rajabi and Shankar, {Suma P.} and Shinawi, {Marwan S.} and {van de Kamp}, {Jiddeke J. P.} and Aravindhan Veerapandiyan and Waldman, {Amy T.} and Graf, {William D.}",
note = "Funding Information: Summary Declaration of Interest Statement: Jacqueline L. Steele, BS: UConn School of Medicine Summer Research Program; Michelle M. Morrow, PhD, Tracy Brandt, PhD, Ganka V. Douglas, PhD, Houda Zghal Elloumi, PhD, and Kristin G. Monaghan, PhD: Employee of GeneDx, Inc; Kenneth A. Myers, MD, PhD: Dr. Myers reports research support from LivaNova and GeneTx, and grants from Dravet Canada, Fonds de Recherches du Qu{\'e}bec–Sant{\'e}, Koolen-de Vries Foundation, Savoy Foundation, Liam Foundation, and Research Institute of the McGill University Health Centre. All other authors declared none. Funding Information: The authors thank the parents who support children with neurodevelopmental disorders such as plexin-related neurogenetic disorders, and all molecular geneticists involved in the analysis and bioinformatic interpretation of genetic variants, including Dr. Boris Keren of H{\^o}pital La Piti{\'e} Salp{\^e}tri{\`e}re, Paris. We thank Carlos E. Prada, MD and Ronald R. Waclaw, PhD from Cincinnati Children's Hospital Medical Center for their support. For this study, Jacqueline L. Steel received a stipend from the University of Connecticut School of Medicine Summer Research Fellowship program. Funding Information: The authors thank the parents who support children with neurodevelopmental disorders such as plexin-related neurogenetic disorders, and all molecular geneticists involved in the analysis and bioinformatic interpretation of genetic variants, including Dr. Boris Keren of H?pital La Piti? Salp?tri?re, Paris. We thank Carlos E. Prada, MD and Ronald R. Waclaw, PhD from Cincinnati Children's Hospital Medical Center for their support. For this study, Jacqueline L. Steel received a stipend from the University of Connecticut School of Medicine Summer Research Fellowship program. Summary Declaration of Interest Statement: Jacqueline L. Steele, BS: UConn School of Medicine Summer Research Program; Michelle M. Morrow, PhD, Tracy Brandt, PhD, Ganka V. Douglas, PhD, Houda Zghal Elloumi, PhD, and Kristin G. Monaghan, PhD: Employee of GeneDx, Inc; Kenneth A. Myers, MD, PhD: Dr. Myers reports research support from LivaNova and GeneTx, and grants from Dravet Canada, Fonds de Recherches du Qu?bec?Sant?, Koolen-de Vries Foundation, Savoy Foundation, Liam Foundation, and Research Institute of the McGill University Health Centre. All other authors declared none. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "1",
doi = "https://doi.org/10.1016/j.pediatrneurol.2021.10.008",
language = "English",
volume = "126",
pages = "65--73",
journal = "Pediatric neurology",
issn = "0887-8994",
publisher = "Elsevier Inc.",
}