A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The RUBCN gene encodes Rubicon, a protein that negatively regulates macroautophagy.
• Pathogenic variants in RUBCN have been linked to spinocerebellar ataxia autosomal recessive 15.

Observation:

• A novel homozygous splice variant (c.2126+1G>A) in RUBCN was identified in a patient with childhood-onset epileptic encephalopathy and neurodevelopmental delay.
• Functional studies revealed the variant abolishes the donor splice site, leading to aberrant transcripts.

Findings:

• The splice variant results in truncated Rubicon protein lacking the conserved Rubicon Homology (RH) domain.
• This disruption likely impairs endosomal trafficking, a previously described mechanism in RUBCN-related disorders.

Implications:

• This is the first report of a splice variant causing RUBCN impairment.
• Identifies a new genetic mechanism for neurodevelopmental disorders and expands the phenotypic spectrum associated with RUBCN.
• Highlights the importance of the RH domain in Rubicon function and its role in neurological health.