Evidence for disease penetrance relating to CNV size: Pelizaeus–Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22
Version of Record online: 20 JUN 2011
© 2011 John Wiley & Sons A/S
Volume 81, Issue 6, pages 532–541, June 2012
How to Cite
Carvalho, C., Bartnik, M., Pehlivan, D., Fang, P., Shen, J. and Lupski, J. (2012), Evidence for disease penetrance relating to CNV size: Pelizaeus–Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22. Clinical Genetics, 81: 532–541. doi: 10.1111/j.1399-0004.2011.01716.x
- Issue online: 4 MAY 2012
- Version of Record online: 20 JUN 2011
- Accepted manuscript online: 30 MAY 2011 05:18AM EST
- Received 18 January 2011, revised and accepted for publication 25 May 2011
- complex rearrangement;
- manifesting female carriers;
- microhomology-mediated break-induced replication;
Carvalho CMB, Bartnik M, Pehlivan D, Fang P, Shen J, Lupski JR. Evidence for disease penetrance relating to CNV size: Pelizaeus–Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22.
The potential causes for the incomplete penetrance of Pelizaeus–Merzbacher disease (PMD) in female carriers of PLP1 mutations are not well understood. We present a family with a boy having PMD in association with PLP1 duplication and three females who are apparent manifesting carriers. Custom high-resolution oligonucleotide array comparative genomic hybridization (aCGH) and breakpoint junction sequencing were performed and revealed a familial complex duplication consisting of a small duplicated genomic interval (∼56 kb) and a large segmental duplication (∼11 Mb) that resulted in a PLP1 copy number variation gain. Breakpoint junction analysis implicates a replication-based mechanism underlying the rearrangement formation. X-inactivation studies (XCI) showed a random to moderate advantageous skewing pattern in peripheral blood cells but a moderate to extremely skewed (≥90%) pattern in buccal cells. In conclusion, our data show that complex duplications involving PLP1 are not uncommon, can be detected at the level of genome resolution afforded by clinical aCGH and duplication and inversion can be produced in the same event. Furthermore, the observation of three manifesting carriers with a large genomic rearrangement supports the contention that duplication size along with genomic content can be an important factor for penetrance of the PMD phenotype in females.