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

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

doi:10.1371/journal.pone.0205298

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 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.

Highlights

The great majority of apparently balanced translocation (ABT) cases are phenotypically normal since theoretically there is no obvious loss or gain of genetic material
Other rarer molecular mechanisms include disruption of an imprinting locus in uniparental disomy (UPD) cases [12], unmasking of recessive gene variants by loss-of-function at the translocation breakpoints leading to functional homozygosity [13], as well as gene fusion generation which may result in a novel, non-functional or pathogenic protein [14]
By using whole-genome mate-pair sequencing (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)

Summary

Introduction

The great majority of apparently balanced translocation (ABT) cases are phenotypically normal since theoretically there is no obvious loss or gain of genetic material. Many molecular mechanisms have been suggested to account for clinical phenotypes observed in ABT carriers. First of all, this may be due to direct disruption of dosage-sensitive genes [3], which exhibit haploinsufficiency [4]. Other rarer molecular mechanisms include disruption of an imprinting locus in uniparental disomy (UPD) cases [12], unmasking of recessive gene variants by loss-of-function at the translocation breakpoints leading to functional homozygosity [13], as well as gene fusion generation which may result in a novel, non-functional or pathogenic protein [14]. The presented phenotypes in ABT carriers may be unrelated to the translocation and coincidental [15]

Objectives

Methods

Results

Conclusion