The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2

Abstract

Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.

Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

“…It was therefore very surprising when recent studies reported massive constitutional chromosomal rearrangements similar to those of chromothripsis in cancer in some patients with congenital developmental disorders (Kloosterman et al 2011a(Kloosterman et al , 2012Chiang et al 2012;Nazaryan et al 2013). In comparison with chromothripsis in cancer, these instances of apparent germline chromothripsis showed minimal DNA loss, presumably reflecting the selection against haploinsufficiency or complete loss of gene function due to monoallelic gene expression.…”

“…The frequency of these types of events in cancer remains unclear, but many recent studies suggest that they may be more common than initially suspected (Malhotra et al 2013;Yang et al 2013;Zack et al 2013). These new classes of mutagenesis are not restricted to human cancer and have turned up in such exotic places as the Tasmanian devil's transmissible facial tumor (Deakin et al 2012) and human congenital diseases (Kloosterman et al 2011a(Kloosterman et al , 2012Liu et al 2011;Chiang et al 2012;Nazaryan et al 2013). Although these new classes of chromosome rearrangement have mostly been found in the context of disease, it seems likely that they reflect very general mechanisms for genome alteration that could be important for organismal evolution.…”

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

“…Though most germline translocations involve only two chromosomes, some are the product of many breakpoints on three to five different chromosomes. Originally seen in cancer (Stephens et al 2011), chromosome shattering or chromothripsis is now recognized as a cause of some germline translocations (Kloosterman et al 2011(Kloosterman et al , 2012Chiang et al 2012;Nazaryan et al 2014;Pellestor et al 2014;de Pagter et al 2015). …”

A germline chromothripsis event stably segregating in 11 individuals through three generations

“…5 Soon after its identification in cancer, CTH was also detected in congenital disorders and was termed "germ-line CTH" (G-CTH). 6,[8][9][10] Whereas CTH is frequently observed in various human cancers, so far there are data from only a few G-CTH cases. Most of these G-CTH events have been observed in complex chromosomal rearrangements, 6,7,9,10 but some have been detected in apparently simple two-way translocations.…”

“…4 Surprisingly, many disease-associated chromosomal rearrangements initially characterized as simple turned out to be more complex than first predicted, revealing a new catastrophic phenomenon of local chromosome shattering termed "chromothripsis" (CTH). [5][6][7][8][9][10] CTH was first characterized in cancerous tissue in which up to hundreds of DNA breaks were localized in relatively small genomic regions and the copy-number states oscillated between one and two (and occasionally three). 5,7 It has been suggested that, in contrast to the progressive model of accumulating mutations in cancer, where rearrangements occur sequentially and independently over many cell cycles, the catastrophic event of CTH happens in a single cell cycle, with profound implications for the etiology of some cancer types.…”