Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

Jacqueline L. Steele; Michelle M. Morrow; Harvey B. Sarnat; Ebba Alkhunaizi; Tracy Brandt; David A. Chitayat; Colette P. DeFilippo; Ganka V. Douglas; Holly A. Dubbs; Houda Zghal Elloumi; Megan R. Glassford; Mark C. Hannibal; B. nédicte Héron; Linda E. Kim; Elysa J. Marco; Cyril Mignot; Kristin G. Monaghan; Kenneth A. Myers; Sumit Parikh; Shane C. Quinonez; Farrah Rajabi; Suma P. Shankar; Marwan S. Shinawi; Jiddeke J. P. van de Kamp; Aravindhan Veerapandiyan; Amy T. Waldman; William D. Graf

doi:10.1016/j.pediatrneurol.2021.10.008

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

Jacqueline L. Steele
, Michelle M. Morrow
, Harvey B. Sarnat
, Ebba Alkhunaizi
, Tracy Brandt
, David A. Chitayat
, Colette P. DeFilippo
, Ganka V. Douglas
, Holly A. Dubbs
, Houda Zghal Elloumi
, Megan R. Glassford
, Mark C. Hannibal
, B. nédicte Héron
, Linda E. Kim
, Elysa J. Marco
, Cyril Mignot
, Kristin G. Monaghan
, Kenneth A. Myers
, Sumit Parikh
, Shane C. Quinonez

Farrah Rajabi, Suma P. Shankar, Marwan S. Shinawi, Jiddeke J. P. van de Kamp, Aravindhan Veerapandiyan, Amy T. Waldman, William D. Graf^*

^*Corresponding author for this work

University of Connecticut
OPKO Health, Inc.
University of Calgary
Mount Sinai Hospital of University of Toronto
University of California at Davis
The Children's Hospital of Philadelphia
University of Michigan Medical School
Hôpital Armand Trousseau
Trillium Health Partners
Department of Neurodevelopmental Medicine, CorticaCare, CA, USA
Sorbonne Université
McGill University
Cleveland Clinic Foundation
Harvard University
Washington University St. Louis
Amsterdam UMC - University of Amsterdam
University of Arkansas for Medical Sciences
Clinical Neuroscience Division, VA National Center for PTSD, VA Connecticut HealthCare System, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
GeneDx
Department of Medical Genetics, and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
Children's Hospital of Philadelphia, Philadelphia, United States
Department of Psychiatry, Michigan Medicine, University of Michigan, Ann Arbor, Michigan.
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, University of Connecticut Health Centre, 400 Farmington Ave, Farmington, CT 06030, USA.
Department of Neurodevelopmental Medicine
Urology, Pitié Salpétrière Hospital, AP-HP, GRC n 5, ONCOTYPE-URO, Sorbonne University, Paris, France.
Montreal Neurological Institute and McGill University Health Centre, McGill University, Montreal, QC, Canada.
Department of Mitochondrial Medicine & Genetics
Harvard
The George Washington University School of Medicine, Washington, DC, USA.
Arkansas Children's Hospital

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	65-73
Number of pages	9
Journal	Pediatric neurology
Volume	126
DOIs	https://doi.org/10.1016/j.pediatrneurol.2021.10.008
Publication status	Published - 1 Jan 2022

Keywords

Autism
Intellectual disability
Neurodevelopment
PLXNA3
Plexin
Semaphorin

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Steele, J. L., Morrow, M. M., Sarnat, H. B., Alkhunaizi, E., Brandt, T., Chitayat, D. A., DeFilippo, C. P., Douglas, G. V., Dubbs, H. A., Elloumi, H. Z., Glassford, M. R., Hannibal, M. C., Héron, B. N., Kim, L. E., Marco, E. J., Mignot, C., Monaghan, K. G., Myers, K. A., Parikh, S., ... Graf, W. D. (2022). Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome. Pediatric neurology, 126, 65-73. https://doi.org/10.1016/j.pediatrneurol.2021.10.008

@article{24c26fbdc89e4358a466fa2e40ef2d04,

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 = "10.1016/j.pediatrneurol.2021.10.008",

language = "English",

volume = "126",

pages = "65--73",

journal = "Pediatric neurology",

issn = "0887-8994",

publisher = "Elsevier Inc.",

}

Steele, JL, Morrow, MM, Sarnat, HB, Alkhunaizi, E, Brandt, T, Chitayat, DA, DeFilippo, CP, Douglas, GV, Dubbs, HA, Elloumi, HZ, Glassford, MR, Hannibal, MC, Héron, BN, Kim, LE, Marco, EJ, Mignot, C, Monaghan, KG, Myers, KA, Parikh, S, Quinonez, SC, Rajabi, F, Shankar, SP, Shinawi, MS, van de Kamp, JJP, Veerapandiyan, A, Waldman, AT & Graf, WD 2022, 'Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome', Pediatric neurology, vol. 126, pp. 65-73. https://doi.org/10.1016/j.pediatrneurol.2021.10.008

TY - JOUR

T1 - Semaphorin-Plexin Signaling

T2 - From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

AU - Steele, Jacqueline L.

AU - Morrow, Michelle M.

AU - Sarnat, Harvey B.

AU - Alkhunaizi, Ebba

AU - Brandt, Tracy

AU - Chitayat, David A.

AU - DeFilippo, Colette P.

AU - Douglas, Ganka V.

AU - Dubbs, Holly A.

AU - Elloumi, Houda Zghal

AU - Glassford, Megan R.

AU - Hannibal, Mark C.

AU - Héron, B. nédicte

AU - Kim, Linda E.

AU - Marco, Elysa J.

AU - Mignot, Cyril

AU - Monaghan, Kristin G.

AU - Myers, Kenneth A.

AU - Parikh, Sumit

AU - Quinonez, Shane C.

AU - Rajabi, Farrah

AU - Shankar, Suma P.

AU - Shinawi, Marwan S.

AU - van de Kamp, Jiddeke J. P.

AU - Veerapandiyan, Aravindhan

AU - Waldman, Amy T.

AU - Graf, William D.

N1 - 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 Québec–Santé, 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 Hôpital La Pitié Salpêtrière, 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: © 2021 The Author(s)

PY - 2022/1/1

Y1 - 2022/1/1

N2 - 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.

AB - 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.

KW - Autism

KW - Intellectual disability

KW - Neurodevelopment

KW - PLXNA3

KW - Plexin

KW - Semaphorin

UR - https://www.scopus.com/pages/publications/85118510423

UR - https://www.ncbi.nlm.nih.gov/pubmed/34740135

UR - https://www.scopus.com/pages/publications/85118510423

U2 - 10.1016/j.pediatrneurol.2021.10.008

DO - 10.1016/j.pediatrneurol.2021.10.008

M3 - Article

C2 - 34740135

SN - 0887-8994

VL - 126

SP - 65

EP - 73

JO - Pediatric neurology

JF - Pediatric neurology

ER -

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

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