@article{3056572,
    title = "Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases",
    author = "Aristidou, C. and Theodosiou, A. and Bak, M. and Mehrjouy, M.M. and Constantinou, E. and Alexandrou, A. and Papaevripidou, I. and Christophidou-Anastasiadou, V. and Skordis, N. and Kitsiou-Tzeli, S. and Tommerup, N. and Sismani, C.",
    journal = "PLOS ONE",
    year = "2018",
    volume = "13",
    number = "10",
    publisher = "Public Library of Science",
    doi = "10.1371/journal.pone.0205298",
    keywords = "NFIB protein, human;  nuclear factor I;  POU3F4 protein, human;  SOX5 protein, human;  transcription factor POU;  transcription factor Sox, case report;  chromosome breakage;  deficiency;  developmental language disorder;  facies;  female;  gene expression;  gene translocation;  genetics;  hearing impairment;  human;  intellectual impairment;  karyotype;  nucleotide sequence;  pathophysiology;  phenotype;  whole genome sequencing, Base Sequence;  Chromosome Breakpoints;  Facies;  Female;  Gene Expression;  Hearing Loss;  Humans;  Intellectual Disability;  Karyotype;  Language Development Disorders;  NFI Transcription Factors;  Phenotype;  POU Domain Factors;  SOXD Transcription Factors;  Translocation, Genetic;  Whole Genome Sequencing",
    abstract = "The majority of apparently balanced translocation (ABT) carriers are phenotypically normal. However, several mechanisms were proposed to underlie phenotypes in affected ABT cases. In the current study, whole-genome mate-pair sequencing (WG-MPS) followed by Sanger sequencing was applied to further characterize de novo ABTs in three affected individuals. WG-MPS precisely mapped all ABT breakpoints and revealed three possible underlying molecular mechanisms. Firstly, in a t(X;1) carrier with hearing loss, a highly skewed Xinactivation pattern was observed and the der(X) breakpoint mapped ∼87kb upstream an Xlinked deafness gene namely POU3F4, thus suggesting an underlying long-range position effect mechanism. Secondly, cryptic complexity and a chromothripsis rearrangement was identified in a t(6;7;8;12) carrier with intellectual disability. Two translocations and a heterozygous deletion disrupted SOX5; a dominant nervous system development gene previously reported in similar patients. Finally, a direct gene disruption mechanism was proposed in a t (4;9) carrier with dysmorphic facial features and speech delay. In this case, the der(9) breakpoint directly disrupted NFIB, a gene involved in lung maturation and development of the pons with important functions in main speech processes. To conclude, in contrast to familial ABT cases with identical rearrangements and discordant phenotypes, where translocations are considered coincidental, translocations seem to be associated with phenotype presentation in affected de novo ABT cases. In addition, this study highlights the importance of investigating both coding and non-coding regions to decipher the underlying pathogenic mechanisms in these patients, and supports the potential introduction of low coverage WGMPS in the clinical investigation of de novo ABTs. © 2018 Aristidou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
}