A de novo Loss-of-function Variant in RAPGEF6 Supports its Role in Neuropsychiatric Disorders

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• RAPGEF6, a guanine nucleotide exchange factor (GEF), interacts with Rap small GTPases and has a Ras/Rap-associating domain.
• Previous studies linked RAPGEF6 deficiency to schizophrenia, but no defined clinical condition is currently associated with it.
• RAPGEF6 is expressed throughout the human brain, involved in neuron projection development and GTPase activity regulation.

Purpose of the Study:

• To investigate the genetic basis of psychiatric disorders and mild intellectual disability in an individual.
• To identify pathogenic variants in genes associated with neurodevelopmental and psychiatric conditions.
• To explore the role of RAPGEF6 in neurodevelopment and neuropsychiatric disorders.

Main Methods:

• Trio-based whole-exome sequencing (WES) was performed on an affected individual and their parents.
• Bioinformatic tools (NMD-Esc predictor, Mutation Taster) were used to predict the effect of the identified variant.
• Developmental transcriptomic data (BrainSpan) and structural variation data (DECIPHER) were analyzed.

Main Results:

• A de novo frameshift variant (c.272dup, p.Pro92Serfs*6) in the RAPGEF6 gene was identified and classified as likely pathogenic.
• The variant is predicted to trigger nonsense-mediated decay (NMD), leading to loss of RAPGEF6 protein.
• Copy-number variants involving RAPGEF6 are associated with intellectual disability and micrognathia, and the gene is intolerant to loss-of-function variants.

Conclusions:

• RAPGEF6 haploinsufficiency may contribute to neurodevelopmental and psychiatric phenotypes.
• The identified variant supports an emerging role for RAPGEF6 in neuropsychiatric disorders.
• Further investigation is needed to fully elucidate the genetic contributions to these complex conditions.