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Mechanisms for Nonrecurrent Genomic Rearrangements Associated with CMT1A or HNPP: Rare CNVs as a Cause for Missing Heritability |
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| Authors: | Feng Zhang Pavel Seeman Marian AJ Weterman Charles F Towne Els De Vriendt Bernd Rautenstrauss Klaus-Henning Krause Jan Posadka Francesc Palau Frank Baas James R Lupski |
| Institution: | 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 2 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China 3 Department of Child Neurology, DNA Laboratory, 2nd School of Medicine, Charles University Prague and University Hospital Motol, V Úvalu 84, 15006 Praha 5, Czech Republic 4 Neurogenetics Lab, Academic Medical Center Amsterdam, 1105 AZ Amsterdam, The Netherlands 5 Athena Diagnositics, Inc., Worcester, MA 01605, USA 6 Department of Molecular Genetics, VIB and University of Antwerp, B-2610 Antwerpen, Belgium 7 Medical Genetics Center, Bayerstrasse 3-5, 80335 Munich, Germany 8 Friedrich-Baur-Institute of the Ludwig-Maximilians-University, Ziemssenstrasse 1, 80336 Munich, Germany 9 Biomnis Inc., F-69357 Lyon, France 10 Institut de Biomedicina, Consejo Superior de Investigaciones Cientificas, and CIBER de Enfermedades Raras (CIBERER), Valencia 46010, Spain 11 Centre de Génétique Humaine, Université de Liège, B-4000 Liège, Belgium 12 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 13 Texas Children's Hospital, Houston, TX 77030, USA |
| Abstract: | Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of “missing heritability” for human diseases. |
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