Potential Link Between a Disruptive CAPN6 Variant and Neurodevelopmental Disorders

Area of Science:

• Genetics and Molecular Biology
• Neurodevelopmental Disorders
• Placental Biology

Background:

• The placenta plays a critical role in fetal neurological development, acting as a "window to the brain."
• Neurodevelopmental and motor coordination disorders were observed in a family across multiple generations.
• Previous research suggests calpain-6 (CAPN6) influences vascular endothelial growth factor (VEGF) activity, impacting fetal development.

Purpose of the Study:

• To investigate the genetic cause of neurodevelopmental disorders in a family with affected offspring.
• To identify the specific gene and variant responsible for the observed phenotypes.
• To explore the potential role of the identified gene in placental function and neurodevelopment.

Main Methods:

• Whole exome sequencing (WES) was performed to identify genetic variants.
• Segregation analysis was conducted to determine the inheritance pattern of the variant.
• Nonsense-mediated mRNA decay (NMD) was assessed to understand the variant's functional impact.

Main Results:

• A disruptive X-linked pathogenic variant (c.1088_1089del p.Asp363GlyfsTer2) in the calpain-6 (CAPN6) gene was identified.
• The variant was found in hemizygous males and heterozygous females within the family, correlating with affected individuals.
• The variant leads to nonsense-mediated mRNA decay (NMD), preventing functional CAPN6 protein production.

Conclusions:

• The identified CAPN6 variant is a potential novel candidate gene for neurodevelopmental disorders.
• CAPN6's role in placental and trophoblast tissues is crucial for fetal development.
• Further functional studies are needed to fully elucidate CAPN6's impact on placental function and neurodevelopment.