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

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.

On the Complexity of Mechanisms and Consequences of Chromothripsis: An Update

“…DSBs are most probably repaired by error-prone NHEJ or microhomology-mediated end joining (MMEJ) mechanisms (Jones and Jallepalli, 2012). In most cases, very short or no microhomology in the chromothripsis breakpoint junctions can be found (Stephens et al, 2011; Chiang et al, 2012; Kloosterman et al, 2012; Malhotra et al, 2013; Weckselblatt et al, 2015; Aristidou et al, 2018; Slamova et al, 2018). However, in a few cases of CC, DSBs were found in high-copy repeats (Nazaryan et al, 2014; Nazaryan-Petersen et al, 2016).…”

The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

“…Additionally, Nfib ‐knockout mouse models have been reported to have agenesis or dysgenesis of the corpus collosum and a reduction in the number of midline glial cells (Piper et al, 2009; Steele‐Perkins et al, 2005). The first reports suggesting that disruption of NFIB (MIM: 618286) may be associated with human phenotypes involved copy number variants (CNVs) and translocations, most of which impacted additional genes and were in patients with heterogeneous phenotypes, making the effects of isolated NFIB disruption difficult to establish (Aristidou et al, 2018; Gobius et al, 2016; Redin et al, 2017; Sajan et al, 2013). In 2018, Schanze and colleagues published a cohort of 18 individuals with pathogenic NFIB variants, including patients with microdeletions and single nucleotide variants (Schanze et al, 2018).…”

A sporadic case of congenital aniridia caused by pericentric inversion inv(11)(p13q14) associated with a 977 kb deletion in the 11p13 region

“…The question of the contribution of PAX6 neighboring genes in the 11p13 region to the manifestation of congenital aniridia remains open. Additionally, when chromosome rearrangements are complex, spatial genomic disorganization could worsen the severity of systemic complications [ 17 , 18 ]. It was recently shown that chromosomal aberrations might not lead to disbalance due to gain or loss of genetic material but rather to the disruption of topologically associating domains (TADs), when a large structural variant might disrupt a CTCF-binding boundary, leading to changes in regulation of unaffected genes [ 19 ].…”