A novel 270 kb deletion upstream of LMNB1 overlapping the ADLD critical regulatory region in two siblings with adult-onset leukodystrophy

Autosomal Dominant Adult-onset Leukodystrophy (ADLD) is a fatal demyelinating disorder classically caused by LMNB1 tandem duplications. Upstream genomic deletions are a less common cause. Although initially attributed to an enhancer-adoption model due to topological boundary disruption, recent studies instead propose that these deletions drive disease by removing a critical 19 kb oligodendrocyte-specific silencer element. We investigated two affected siblings with an adult-onset leukodystrophy compatible with ADLD who remained undiagnosed after exome sequencing. Genome sequencing was performed to identify pathogenic structural variants, followed by molecular validation, blood RNA sequencing and sequence-based prediction of chromatin contacts. Genome sequencing identified a novel heterozygous ~ 270 kb upstream deletion encompassing the recently defined LMNB1 oligodendrocyte-specific silencer while preserving the LMNB1 coding sequence. The deleted interval contains the 167 kb region shared by all previously reported upstream deletions and ends 17 kb upstream of the LMNB1 transcription start site. The deletion was confirmed by chromosomal microarray and by junction PCR with Sanger sequencing in both siblings, and was classified as likely pathogenic. Peripheral blood RNA sequencing showed no evidence of increased LMNB1 expression, consistent with the previously described tissue-specific regulatory mechanism for this silencer. This study expands the spectrum of pathogenic upstream regulatory variants associated with LMNB1 -related ADLD and provides additional clinical evidence for the involvement of the critical upstream regulatory region in disease pathogenesis. Dosage analysis covering the region upstream of LMNB1 , and not only the gene itself, should be part of the workup of suspected ADLD.