A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay

ABSTRACTThe RUBCN gene encodes a widely expressed protein called Rubicon, the main function of which is to negatively regulate macroautophagy. A single homozygous pathogenic variant of the RUBCN gene has been reported to date in two unrelated consanguineous Saudi families with spinocerebellar ataxia autosomal recessive 15 (OMIM#613516). This variant is responsible for the deletion of the highly conserved Rubicon Homology (RH) domain, which is important for the colocalization of Rubicon with Rab7 in the late endosome. In this work, we describe a female patient with childhood‐onset epileptic encephalopathy and neurodevelopmental delay carrying a novel homozygous variant in RUBCN (NM_014687.3: c.2126 + 1G>A). A functional study of the RNA revealed that this variant completely abolishes the consensus donor site at the exon 14/intron 14 junction, resulting in the absence of expression of the reference transcript. Two alternative transcripts were expressed: a major transcript resulting from activation of an alternative exonic splice site and a minor transcript with skipping of exon 14. The two alternative transcripts lead to a shift in the reading frame introducing a premature stop codon. The resulting truncated protein lacks the RH domain, which may lead to defective endosomal trafficking as previously described. To our best knowledge, this is the first report of an impairment of RUBCN caused by a splice variant.