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

Area of Science:

• Neurogenetics
• Developmental Neuroscience

Background:

• Semaphorins and plexins are crucial for neurodevelopment, including axonal growth and guidance.
• PLXNA3, encoding plexin-A3, is widely expressed in the fetal brain and plays a role in semaphorin signaling.
• The clinical impact of semaphorin/plexin gene variants on neurodevelopmental disorders is not fully understood.

Purpose of the Study:

• To investigate the neurological and neurodevelopmental phenotypes associated with maternally inherited hemizygous PLXNA3 variants in boys.
• To explore the clinical manifestations of a potential novel X-linked intellectual disability syndrome.

Main Methods:

• Utilized data-sharing platforms (GeneDx, GeneMatcher) to identify affected individuals.
• Collected clinical data via questionnaires from physicians and genetic counselors for 14 boys with autism/intellectual disability (autism/ID) and PLXNA3 variants.
• Performed in silico analyses to predict the pathogenicity of identified PLXNA3 variants.

Main Results:

• Assessed 14 boys with maternally inherited hemizygous PLXNA3 variants, presenting with autism/ID, fine motor dyspraxia, attention-deficit/hyperactivity traits, and aggressive behaviors.
• Observed seizures in 43% of patients; 93% had novel or low-frequency variants predicted as damaging.
• Found a significant genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants and more severe neurodevelopmental outcomes (P < 0.05).

Conclusions:

• Reported 14 boys with maternally inherited hemizygous PLXNA3 variants, suggesting a novel X-linked intellectual disability syndrome.
• Highlighted the association between PLXNA3 variants and a spectrum of neurodevelopmental disorders.
• Emphasized the need for further clinical, computational, and experimental validation to fully understand PLXNA3 variant pathogenicity in humans.