PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder

Area of Science:

• Neurogenetics
• Genomic Medicine
• Developmental Neuroscience

Background:

• Autism spectrum disorder (ASD) is a neurodevelopmental condition with high heritability, but its genetic underpinnings remain largely unknown.
• Elucidating novel genotype-phenotype relationships is crucial for advancing ASD etiological understanding and diagnostic capabilities.

Purpose of the Study:

• To identify genetic variants associated with a complex neurobehavioral phenotype in an autism spectrum disorder (ASD) patient.
• To investigate the functional consequences of identified variants in candidate genes PLXNA2 and LRRC40.

Main Methods:

• Copy-number variant and whole-exome sequencing were performed on an ASD patient presenting with epilepsy and attention deficit hyperactivity disorder.
• In silico analysis predicted the pathogenicity of identified variants.
• mRNA and protein expression, subcellular localization, and protein-protein interactions were studied in patient and control fibroblasts.

Main Results:

• Rare recessive variants in PLXNA2 (Plexin A2) and LRRC40 (Leucine-rich repeat containing protein 40) were identified in the patient.
• Patient fibroblasts showed PlxnA2 subcellular delocalization and significantly reduced LRRC40 protein levels.
• A novel interaction between PlxnA2 and LRRC40 was discovered, which was diminished in the patient's cells, suggesting a shared neural pathway.

Conclusions:

• PLXNA2 and LRRC40 are identified as candidate genes contributing to ASD pathogenesis.
• The findings provide new insights into the molecular mechanisms underlying ASD, particularly in cases with complex phenotypes.
• Further investigation of PLXNA2 and LRRC40 is warranted in genetic studies of neurodevelopmental disorders, including ASD.