ClinVar Genomic variation as it relates to human health

In 2 families of Irish American descent and in 2 other families with autosomal dominant adult-onset leukodystrophy (169500), Padiath et al. (2006) found a duplication of the LMNB1 gene and part of the MARCH3 gene (613333). Haplotype analysis suggested that the 2 Irish American families arose through a common founder. In affected members of 4 unrelated families with ADLD, Schuster et al. (2011) found duplication of the LMNB1 gene and part of the MARCH3 gene. All 4 duplications were of different sizes, ranging from 107 to 218 kb, supporting independent events. Five patients from 2 families had about a 2-fold increased level of LMNB1 protein in white blood cells, and LMNB1 mRNA was also increased compared to controls. MARCH3 mRNA was not increased in patient leukocytes. Schuster et al. (2011) concluded that an accurate molecular diagnosis of the disorder could be made by direct analysis of LMNB1 in peripheral leukocytes. In a symptomatic man with ADLD and his asymptomatic sister who had leukodystrophy on brain imaging, Dos Santos et al. (2012) identified a 148-kb duplication on chromosome 5q23.2 including the LMNB1 gene, but not the MARCH3 gene. The findings confirmed the central role of the LMNB1 gene in ADLD. Using a custom array, Giorgio et al. (2013) performed detailed breakpoint junction sequence analysis of the duplicated 5q23 region containing the LMNB1 gene in 20 independent families with ADLD in whom genomic LMNB1 duplication was initially identified by aCGH, QT-PCR, or MLPA. Seven families had previously been reported (Brussino et al., 2009; Schuster et al., 2011; Dos Santos et al., 2012). There were a total of 16 unique rearrangements. Three of the duplications were shared by more than 1 family: 1 was found in 3 families and the other 2 duplications were found in 2 families each. Individuals with identical junctions shared the same haplotype, consistent with a founder effect. Duplication sizes ranged from about 128 kb to 475 kb. The largest duplication also included the PHAX (604924), ALDH7A1 (107323), and GRAMD3 genes. Comparison of all the samples identified a 72-kb minimal critical duplicated region required for ADLD that contained only the LMNB1 gene. All but 1 of the duplications were in the direct tandem orientation; the remaining duplication was inverted. Characterization of the junction sequences showed that most (11 of 15) showed short stretches of microhomology overlap ranging from 1 to 6 nucleotides, whereas the others showed small insertions at the breakpoints. All duplications resulted from intrachromosomal rearrangements. Analysis of the genomic architecture suggested several potential mechanisms for the duplications, including nonhomologous end joining (NHEJ) or fork stalling and template switching/microhomology-mediated break-induced repair (FoSTeS/MMBIR). The enrichment of Alu repetitive elements at the centromeric breakpoints (found in 4 cases), higher GC content, and high frequency of repetitive sequences at breakpoints likely also played a role in mediating ADLD duplications. RT-PCR of patients fibroblasts or blood showed increased LMNB1 expression (2.1- to 4.8-fold compared to controls), as well as increased protein levels (1.6- to 3.2-fold compared to controls). There was no apparent difference in phenotype according to duplication size, with the exception of the 1 family with a large inverted duplication affecting multiple genes. (less)