Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases

TY - JOUR

T1 - Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases

AU - Aristidou, Constantia

AU - Theodosiou, Athina

AU - Bak, Mads

AU - Mehrjouy, Mana M.

AU - Constantinou, Efthymia

AU - Alexandrou, Angelos

AU - Papaevripidou, Ioannis

AU - Christophidou-Anastasiadou, Violetta

AU - Skordis, Nicos

AU - Kitsiou-Tzeli, Sophia

AU - Tommerup, Niels

AU - Sismani, Carolina

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0205298

DO - 10.1371/journal.pone.0205298

M3 - Journal article

C2 - 30289920

AN - SCOPUS:85054439624

SN - 1932-6203

VL - 13

JO - PLOS ONE

JF - PLOS ONE

IS - 10

M1 - e0205298

ER -