{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:54:48Z","timestamp":1791618888198,"version":"4.3.4"},"reference-count":34,"publisher":"BMJ","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2009,11,5]]},"published-print":{"date-parts":[[2010,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Localisation of the breakpoints of chromosomal translocations has aided the discovery of several disease genes but has traditionally required laborious investigation of chromosomes by fluorescent in situ hybridisation approaches. Here, a strategy that utilises genome-wide paired-end massively parallel DNA sequencing to rapidly map translocation breakpoints is reported. This method was used to fine map a de novo t(5;6)(q21;q21) translocation in a child with bilateral, young-onset Wilms tumour.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Genome-wide paired-end sequencing was performed for approximately 6 million randomly generated \u223c3\u2005kb fragments from constitutional DNA containing the translocation, and six fragments in which one end mapped to chromosome 5 and the other to chromosome 6 were identified. This mapped the translocation breakpoints to within 1.7\u2005kb. Then, PCR assays that amplified across the rearrangement junction were designed to characterise the breakpoints at sequence-level resolution. The 6q21 breakpoint transects and truncates <jats:italic>HACE1<\/jats:italic>, an E3 ubiquitin-protein ligase that has been implicated as a somatically inactivated target in Wilms tumourigenesis. To evaluate the contribution of <jats:italic>HACE1<\/jats:italic> to Wilms tumour predisposition, the gene was mutationally screened in 450 individuals with Wilms tumour. One child with unilateral Wilms tumour and a truncating <jats:italic>HACE1<\/jats:italic> mutation was identified.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These data indicate that constitutional disruption of <jats:italic>HACE1<\/jats:italic> likely predisposes to Wilms tumour. However, <jats:italic>HACE1<\/jats:italic> mutations are rare and therefore can only make a small contribution to Wilms tumour incidence. More broadly, this study demonstrates the utility of genome-wide paired-end sequencing in the delineation of apparently balanced chromosomal translocations, for which it is likely to become the method of choice.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2009.072983","type":"journal-article","created":{"date-parts":[[2009,11,30]],"date-time":"2009-11-30T20:25:17Z","timestamp":1259612717000},"page":"342-347","source":"Crossref","is-referenced-by-count":51,"title":["Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies <i>HACE1<\/i> as a putative Wilms tumour susceptibility 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