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

Date Published: October 5, 2018

Publisher: Public Library of Science

Author(s): Constantia Aristidou, Athina Theodosiou, Mads Bak, Mana M. Mehrjouy, Efthymia Constantinou, Angelos Alexandrou, Ioannis Papaevripidou, Violetta Christophidou-Anastasiadou, Nicos Skordis, Sophia Kitsiou-Tzeli, Niels Tommerup, Carolina Sismani, Swati Palit Deb.


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 X-inactivation pattern was observed and the der(X) breakpoint mapped ~87kb upstream an X-linked 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 WG-MPS in the clinical investigation of de novo ABTs.

Partial Text

The great majority of apparently balanced translocation (ABT) cases are phenotypically normal since theoretically there is no obvious loss or gain of genetic material. However, association with specific clinical phenotypes has been originally estimated in 6–10% of de novo ABT cases [1], while recent studies assessing long-term outcomes in de novo ABT carriers estimated a morbidity risk of 27% [2].

By using WG-MPS, translocation breakpoint junctions in all three affected de novo ABT carriers included in the present study were successfully identified and mapped down to a region ranging between 407bp and 1.9kb (Table 1). Direct and indirect disease-candidate gene disruption occurred in 2/3 and 1/3 cases, respectively, while cryptic complexity was identified in 1/3 cases. Microhomology (1-5bp) and imbalances (1-6bp) were also detected at the translocation breakpoint sites (Table 1). Detailed results are presented below:

In contrast to our recent findings concerning familial cases with identical ABTs and discordant phenotypes [15], breakpoint mapping results from the present study demonstrated that translocations appear to be correlated with phenotype presentation in de novo ABT cases. This is achieved through a number of underlying molecular mechanisms including LRPE, cryptic complexity, and direct disease-associated gene disruption by the translocation breakpoints.




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