HUMAN KVLQT1 GENE SHOWS TISSUE-SPECIFIC IMPRINTING AND ENCOMPASSES BECKWITH-WIEDEMANN SYNDROME CHROMOSOMAL REARRANGEMENTS

Genomic imprinting is an epigenetic chromosomal modification in the ga mete or zygote causing preferential expression of a specific parental allele in somatic cells of the offspring. We and others have identifie d three imprinted human genes on 11p15.5, IGF2 (refs 1-4), H19 (refs 1 ,5), and p57(KIP2) (ref. 6), although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other i mprinted genes within this large interval. We previously mapped an emb ryonal tumour suppressor gene to this region(7), as well as five balan ced germline chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann syndrome (BWS)(8), a condition characterized by pre natal overgrowth and cancer. We isolated the upstream exons of the pre viously identified gene KVLQT1, which causes the familial cardiac defe ct long-QT (LQT) syndrome. We found that KVLQT1 spans much of the inte rval between p57(KIP2) and IGF2, and that it is also imprinted. We dem onstrated that the gene is disrupted by chromosomal chromosomal transl ocation in an embryonal rhabdoid tumour. Furthermore, the lack of pare nt-of-origin effect in LQT syndrome appears to be due to relative lack of imprinting in the affected tissue, cardiac muscle, representing a novel mechanism for variable penetrance of a human disease gene.