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Genome Med. 2019 Dec 9;11(1):80. doi: 10.1186/s13073-019-0676-0.

Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.

Author information

1
Graduate Program in Diagnostic Genetics, School of Health Professions, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Present address: Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center UTHealth, Houston, TX, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX, USA.
4
Nemours Biomedical Research, Nemours/Alfred I. DuPont Hospital for Children, 1600 Rockland Road, RC1, Wilmington, DE, USA.
5
Present address: Department of Genetics and Genome Sciences, University of Connecticut Health Center and the Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
6
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR.
7
DNA Laboratory, Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, 150 06, Prague, Czech Republic.
8
Clinical and Molecular Genetics Unit, Institute of Child Health, London, UK.
9
Present address: Diagnostic Genomics, PathWest Laboratory Medicine, Perth, WA, Australia.
10
School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
11
Nemours Biomedical Research, Nemours/Alfred I. DuPont Hospital for Children, 1600 Rockland Road, RC1, Wilmington, DE, USA. Grace.Hobson@nemours.org.
12
Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. Grace.Hobson@nemours.org.
13
Department of Biological Sciences, University of Delaware, Newark, DE, USA. Grace.Hobson@nemours.org.
14
Graduate Program in Diagnostic Genetics, School of Health Professions, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Jlupski@bcm.edu.
15
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX, USA. Jlupski@bcm.edu.
16
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Jlupski@bcm.edu.
17
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. Jlupski@bcm.edu.
18
Texas Children's Hospital, Houston, TX, USA. Jlupski@bcm.edu.

Abstract

BACKGROUND:

We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied. Analysis of these data from 150 individuals enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated.

METHODS:

Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array or clinical chromosomal microarray analysis and breakpoint junction sequence analysis.

RESULTS:

High-density customized array showed that the majority of cases (33/50; ~ 66%) present with single duplications, although complex genomic rearrangements (CGRs) are also frequent (17/50; ~ 34%). Breakpoint mapping to nucleotide resolution revealed further previously unknown structural and sequence complexities, even in single duplications. Meta-analysis of all studied rearrangements that occur at the PLP1 locus showed that single duplications were found in ~ 54% of individuals and that, among all CGR cases, triplication flanked by duplications is the most frequent CGR array CGH pattern observed. Importantly, in ~ 32% of join-points, there is evidence for a mutational signature of microhomeology (highly similar yet imperfect sequence matches).

CONCLUSIONS:

These data reveal a high frequency of CGRs at the PLP1 locus and support the assertion that replication-based mechanisms are prominent contributors to the formation of CGRs at Xq22. We propose that microhomeology can facilitate template switching, by stabilizing strand annealing of the primer using W-C base complementarity, and is a mutational signature for replicative repair.

KEYWORDS:

BIR; Duplication; Genome instability; Genomic rearrangements; HR; LCR; MMBIR; Microhomeology; PMD; RBM

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