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. 2022 Jan:126:65-73.
doi: 10.1016/j.pediatrneurol.2021.10.008. Epub 2021 Oct 18.

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

Jacqueline L Steele  1 , Michelle M Morrow  2 , Harvey B Sarnat  3 , Ebba Alkhunaizi  4 , Tracy Brandt  2 , David A Chitayat  4 , Colette P DeFilippo  5 , Ganka V Douglas  2 , Holly A Dubbs  6 , Houda Zghal Elloumi  2 , Megan R Glassford  7 , Mark C Hannibal  7 , Bénédicte Héron  8 , Linda E Kim  9 , Elysa J Marco  10 , Cyril Mignot  11 , Kristin G Monaghan  2 , Kenneth A Myers  12 , Sumit Parikh  13 , Shane C Quinonez  7 , Farrah Rajabi  14 , Suma P Shankar  5 , Marwan S Shinawi  15 , Jiddeke J P van de Kamp  16 , Aravindhan Veerapandiyan  17 , Amy T Waldman  6 , William D Graf  18
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Free article

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

Jacqueline L Steele et al. Pediatr Neurol. 2022 Jan.
Free article

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.

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