PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl

Abstract

PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus-Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array-based comparative genomic hybridization (a-CGH), we detected duplications at 22q13 and Xq22, encompassing 487-546 kb and 543-611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X-chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X-inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.

A Cytogenomic Approach in a Case of Syndromic XY Gonadal Dysgenesis

“…The majority of the men and more than half of the women with this condition are infertile [Dutta et al, 2012]. Translocations involving chromosome 22 and the X chromosome have been reported in literature, although there has been only one case of a female with a karyotype 46,XY,der(22),t(X;22)(pl1.3;pl1) [Pinto et al, 1989;Baumstark et al, 1996;Fonseca et al, 2013]. This is the first report of a female patient with XY chromosomes and Xp duplication involving the DAX1 gene due to X;22 translocation.…”

Pelizaeus–Merzbacher disease as a chromosomal disorder

“…; Fonseca et al. ). Such chromosomal rearrangements should be investigated by fluorescence in situ hybridization (FISH) method, because otherwise, accurate genetic counseling cannot be provided.…”

“…In very rare cases, chromosomal translocations involving the PLP1 region have been identified (Hodes et al 2000;Ida et al 2003;Woodward et al 2003;Fonseca et al 2012). Such chromosomal rearrangements should be investigated by fluorescence in situ hybridization (FISH) method, because otherwise, accurate genetic counseling cannot be provided.…”

Genomic Investigation of Balanced Chromosomal Rearrangements in Patients with Abnormal Phenotypes

“…Microarray based studies reported copy number variations (microdeletions or microduplications) at the breakpoint(s) of BCR and at other genomic regions far from the breakpoints [Gribble et al, 2005;De Gregori et al, 2007;Baptista et al, 2008;Schluth-Bolard et al, 2009;Fonseca et al, 2013]. These alterations elucidated the abnormal phenotype in 30-50% of the carriers.…”