Implication of LRRC4C and DPP6 in neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Autism Spectrum Disorder (ASD) and other neurodevelopmental disorders (NDDs) are complex genetic conditions.
• Identifying specific gene disruptions is crucial for understanding disease mechanisms and potential therapeutic targets.

Purpose of the Study:

• To investigate the genetic underpinnings of variable psychiatric phenotypes, including sensory processing disorder, apraxia, and autism, within a single family.
• To identify novel gene variants associated with NDDs through whole-genome sequencing and copy number analysis.

Main Methods:

• Whole-genome sequencing of an affected individual and family members.
• Copy Number (CN) analysis comparing 14,077 NDD cases with 8,960 controls.
• In vitro functional assessments of gene deletions.

Main Results:

• A balanced translocation disrupted LRRC4C (netrin G family, axon guidance) and a chromosomal inversion disrupted DPP6 (potassium channel interacting protein) in the proband.
• Exonic deletions in LRRC4C were found in 60% of NDD cases with co-occurring clinically recognizable syndromes, suggesting a modifier role.
• In vitro studies indicated a negative regulatory function for specific LRRC4C exons.

Conclusions:

• The proband's autism may result from combined disruptions in DPP6 and LRRC4C.
• Netrin G family members and potassium channel interacting molecules are highlighted as important in neurodevelopmental disorders.
• LRRC4C deletion variants may act as modifiers in NDDs with syndromic features.