Researchers have identified a previously unreported genetic deletion in two siblings with a fatal adult-onset demyelinating disorder, adding a new entry to the short list of structural variants known to cause Autosomal Dominant Adult-onset Leukodystrophy, or ADLD. The finding, published in BMC Neurology, centers not on a gene itself but on a stretch of DNA lying upstream of LMNB1, the gene classically implicated in the disease.
Upstream genomic deletions are a less common cause of the same condition. For years these deletions were explained by an enhancer-adoption model, in which the removal of a topological boundary allowed distant regulatory elements to abnormally activate LMNB1. More recent studies, however, propose a different mechanism: the deletions cause disease by removing a critical 19 kb oligodendrocyte-specific silencer element, a regulatory sequence that normally restrains LMNB1 activity in the myelin-producing cells of the brain.
The two affected siblings in the new study had an adult-onset leukodystrophy compatible with ADLD but remained undiagnosed after exome sequencing, the standard first-line test that reads only the protein-coding portions of the genome. Because exome sequencing misses large structural rearrangements, the team turned to whole genome sequencing to search for pathogenic structural variants, followed by molecular validation, blood RNA sequencing, and sequence-based prediction of chromatin contacts.
Genome sequencing revealed a novel heterozygous deletion of roughly 270 kb located upstream of LMNB1. The deleted interval encompasses the recently defined LMNB1 oligodendrocyte-specific silencer while preserving the LMNB1 coding sequence intact. Notably, the deletion contains the 167 kb region shared by all previously reported upstream deletions and ends 17 kb upstream of the LMNB1 transcription start site, placing it squarely within the critical regulatory region associated with the disease.
The variant was confirmed by two independent methods in both siblings: chromosomal microarray, which detects copy-number changes across the genome, and junction PCR with Sanger sequencing, which reads across the deletion breakpoints directly. Based on this evidence, the deletion was classified as likely pathogenic.
A key molecular observation came from peripheral blood RNA sequencing, which showed no evidence of increased LMNB1 expression in blood cells. The researchers interpret this as consistent with the previously described tissue-specific regulatory mechanism for the silencer: the element acts in oligodendrocytes, so its loss would be expected to deregulate LMNB1 in those brain cells rather than in circulating blood, where the deletion carriers show no expression change.
The study expands the spectrum of pathogenic upstream regulatory variants associated with LMNB1-related ADLD and provides additional clinical evidence that the critical upstream regulatory region is involved in disease pathogenesis. Each newly reported deletion that overlaps the shared 167 kb interval strengthens the case that loss of this regulatory element, rather than disruption of topological boundaries alone, underlies the disorder in deletion carriers.
The authors draw a practical diagnostic conclusion from the finding: dosage analysis covering the region upstream of LMNB1, and not only the gene itself, should be part of the workup of suspected ADLD. For families like the one described here, in which exome sequencing fails to yield a diagnosis, genome sequencing combined with targeted analysis of the upstream regulatory region may be required to detect variants of this class. The article was published open access on 29 October 2026 as a peer-reviewed research article in BMC Neurology by Ayca Yigit, Mert Pekerbas, Burcu Akman, Baris Salman, Zeki Sakalli, Sinem Sisko, Mehmet Berkay Akcan, Ayca Aykut, Asude Durmaz, Haluk Akin and Ugur Ozbek, with Yigit and Pekerbas listed as co-first authors.
Subject of Research: A novel upstream deletion of LMNB1 removing an oligodendrocyte-specific silencer element in siblings with adult-onset leukodystrophy
Article Title: A novel 270 kb deletion upstream of LMNB1 overlapping the ADLD critical regulatory region in two siblings with adult-onset leukodystrophy
Article References: Yigit, A., Pekerbas, M., Akman, B., Salman, B., Sakalli, Z., Sisko, S., Akcan, M. B., Aykut, A., Durmaz, A., Akin, H., & Ozbek, U. (2026). A novel 270 kb deletion upstream of LMNB1 overlapping the ADLD critical regulatory region in two siblings with adult-onset leukodystrophy. BMC Neurology. https://doi.org/10.1186/s12883-026-05576-z
Image Credits: AI Generated
DOI: 10.1186/s12883-026-05576-z
Keywords: LMNB1, ADLD, leukodystrophy, genome sequencing, structural variant, silencer element, oligodendrocyte, demyelination, chromosomal microarray, RNA sequencing, BMC Neurology, novel
News Source: Juliet Wilcox. (October 29, 2026). Novel 270 kb deletion upstream of LMNB1 linked to adult-onset leukodystrophy in two siblings. Scienmag.
