Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus‐Merzbacher disease

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Abstract
We report cytogenetic and molecular findings in a family in which Pelizaeus‐Merzbacher disease has arisen by a sub‐microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of ∼600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived X chromosome and was inherited by her son, the proband, who is affected with Pelizaeus‐Merzbacher disease. The mother also carries a large interstitial deletion of ∼70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication X chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter → Xq26.3::Xq22 → Xq22::Xq26.3 → Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP−). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected DNA clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.