NRXN3 mutations cause developmental delay, movement disorder, and behavioral problems: CRISPR edited cells based WES...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• NRXN3 encodes neurexin-III, a neural cell adhesion molecule crucial for synaptic function.
• Neurexin-III deficiency can impact synapse development, signaling, and neurotransmitter release.
• No OMIM-listed disorders were previously associated with NRXN3 mutations.

Purpose of the Study:

• To identify and characterize novel genetic variants in the NRXN3 gene.
• To investigate the pathogenicity of identified NRXN3 variants.
• To establish a link between NRXN3 mutations and a syndromic mendelian disorder.

Main Methods:

• Genetic analysis of two unrelated Iranian families.
• Next-Generation Sequencing (NGS) to detect variants in the NRXN3 gene.
• Functional studies including CRISPR-edited cells and in-silico analysis.
• Phenotypic correlation with homozygous Nrxn3 knockout mouse models.

Main Results:

• Identified homozygous and compound heterozygous variants in NRXN3 in affected individuals.
• Observed phenotypes include learning disability, developmental delay, movement disorders, and behavioral problems.
• Functional studies and mouse model data support the pathogenicity of NRXN3 variants.

Conclusions:

• Homozygous and compound heterozygous mutations in NRXN3 cause a novel autosomal recessive syndromic genetic disorder.
• Key clinical features include developmental delay, learning disability, movement disorder, and behavioral problems.
• This study establishes neurexin-III deficiency as a cause of a new mendelian disorder.