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; Bénédicte 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, Bénédicte Héron, Linda E. Kim, Elysa J. Marco, Cyril Mignot, Kristin G. Monaghan, Kenneth A. Myers, Sumit Parikh, Shane C. QuinonezFarrah Rajabi, Suma P. Shankar, Marwan S. Shinawi, Jiddeke J.P. van de Kamp, Aravindhan Veerapandiyan, Amy T. Waldman, William D. Graf

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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
State	Published - Jan 2022

Keywords

Autism
Intellectual disability
Neurodevelopment
PLXNA3
Plexin
Semaphorin

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10.1016/j.pediatrneurol.2021.10.008

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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., 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{90e82ef19f3d45b484c5c82eeed42109,

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 B{\'e}n{\'e}dicte H{\'e}ron 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 = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = jan,

doi = "10.1016/j.pediatrneurol.2021.10.008",

language = "English",

volume = "126",

pages = "65--73",

journal = "Pediatric Neurology",

issn = "0887-8994",

}

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, B, 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, Bénédicte

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.

PY - 2022/1

Y1 - 2022/1

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 - http://www.scopus.com/inward/record.url?scp=85118510423&partnerID=8YFLogxK

U2 - 10.1016/j.pediatrneurol.2021.10.008

DO - 10.1016/j.pediatrneurol.2021.10.008

M3 - Article

C2 - 34740135

AN - SCOPUS:85118510423

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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