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. 2025 Apr 17;11(3):e200261.
doi: 10.1212/NXG.0000000000200261. eCollection 2025 Jun.

Atypical Presentation of an LMNB1 Duplication Involving the Silencer Region: Beyond Classical Autosomal-Dominant Leukodystrophy

Affiliations

Atypical Presentation of an LMNB1 Duplication Involving the Silencer Region: Beyond Classical Autosomal-Dominant Leukodystrophy

Jia Dong James Wang et al. Neurol Genet. .

Abstract

Objectives: The aim of this study was to characterize the clinical, genetic, and radiologic presentation of a patient with LMNB1 gene duplication, including the duplication of the silencer region.

Methods: A patient who presented with muscle stiffness and constipation underwent comprehensive clinical and imaging evaluations, followed by next-generation whole-genome sequencing and optical genome mapping. In the subsequent year, the proband reported additional symptoms of muscle spasms, difficulty of relaxation of the anal sphincter, and stiffness in movements.

Results: MRI of the brain demonstrated mild diffuse white matter hyperintensities bilaterally. Analysis of optical genome mapping data revealed a 275.54-kb tandem duplication at 5q23.2 [NC_000005.10:g.126637655_126913191dup] comprising 4 genes including the LMNB1 gene.

Discussion: We identified a 69-year-old patient with an LMNB1 duplication who presented with a milder phenotype compared with typical LMNB1-related autosomal-dominant leukodystrophy. The symptoms included dysautonomia and muscle stiffness. This distinct presentation is likely attributable to the duplication of the silencer region of LMNB1, which may contribute to the milder symptoms observed.

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures.

Figures

Figure 1
Figure 1. MRI of the Brain
MRI brain performed at baseline (A) and at 2 years (B) with T2-weighted and fluid-attenuated inversion recovery (FLAIR) images presented. The images on the left correspond to T2-weighted sequences while those on the right represent FLAIR sequences.
Figure 2
Figure 2. Tandem Duplications on Chromosome 5: Novel ADLD Duplication Extending LMNB1 Regulatory Region
The figure illustrates tandem duplications on chromosome 5 in the hg38 reference genome. The blue bars represent previously described large “no ADLD” tandem duplications. By contrast, the novel “no ADLD” tandem duplication identified in this study is highlighted in red. The green bar highlights the previously reported 19-kb silencer region. The purple bar denotes the region where most ADLD-related duplications have been observed. Black lines indicate gene positions along chromosome 5 while red lines highlight genes duplicated within this case. Compared with ADLD-related duplications, these “no ADLD” tandem duplications are larger and encompass more of the upstream regulatory region of LMNB1, extending further toward the centromeric end. The arrow within the blue bar indicates that the duplication extends upstream in the 5′ direction.

References

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