Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• NTNG2 encodes netrin-G2, a protein crucial for neuronal circuitry and synaptic development in vertebrates.
• Disruptions in neuronal organization can lead to neurodevelopmental disorders.

Purpose of the Study:

• To identify the genetic cause of a shared neurodevelopmental disorder observed in 16 individuals from seven families.
• To investigate the role of NTNG2 variants in neurodevelopmental phenotypes.

Main Methods:

• Exome sequencing and autozygosity mapping were used to identify homozygous missense variants in the NTNG2 gene.
• In silico protein structure analysis, in vitro cell surface expression, and in vitro knockdown experiments were performed.

Main Results:

• Ultra-rare homozygous missense variants in NTNG2 were identified in all affected individuals.
• These variants affect highly conserved residues and lead to loss of protein function and decreased neurite outgrowth.
• Affected individuals presented with global developmental delay, intellectual disability, muscle weakness, autistic features, and dysmorphisms.

Conclusions:

• Homozygous NTNG2 variants are pathogenic and cause a distinct neurodevelopmental disorder.
• Proper NTNG2 expression is essential for neurotypical development.
• This study expands the genetic understanding of neurodevelopmental disorders.