Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene 
underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a 
rare neurological disorder in which overexpression of LMNB1 causes progressive 
central nervous system demyelination. However, we previously reported an ADLD 
family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 
despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom 
array-CGH, we further investigated this family and report here that patients 
carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the 
LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO 
tissues and in a postmortem brain sample, where lamin B1 was increased in the 
frontal lobe. Through parallel studies, we investigated both loss of genetic 
material and chromosomal rearrangement as possible causes of LMNB1 
overexpression, and found that ADLD-1-TO plausibly results from an enhancer 
adoption mechanism. The deletion eliminates a genome topological domain 
boundary, allowing normally forbidden interactions between at least three 
forebrain-directed enhancers and the LMNB1 promoter, in line with the observed 
mainly cerebral localization of lamin B1 overexpression and myelin degeneration. 
This second route to LMNB1 overexpression and ADLD is a new example of the 
relevance of regulatory landscape modifications in determining Mendelian 
phenotypes.