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Background  Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by disturbances of the chromosomal region 11p15.5. The most frequent molecular finding in BWS is loss of methylation (LOM) of the Imprinting Centre 2 (IC2) region on the maternal allele, which is localised in intron 10 of the  KCNQ1  gene. In rare cases, LOM of IC2 has been reported in families with  KCNQ1  germline variants which additionally cause long-QT syndrome (LQTS). Thus, a functional link between disrupted  KCNQ1  transcripts and altered IC2 methylation has been suggested, resulting in the co-occurrence of LQTS and BWS in case of maternal inheritance. Whereas these cases were identified by chance or in patients with abnormal electrocardiograms, a systematic screen for  KCNQ1  variants in IC2 LOM carriers has not yet been performed.    Results  We analysed 52 BWS patients with IC2 LOM to determine the frequency of germline variants in  KCNQ1  by MLPA and an amplicon-based next generation sequencing approach. We identified one patient with a splice site variant causing premature transcription termination of  KCNQ1 .    Conclusions  Our study strengthens the hypothesis that proper  KCNQ1  transcription is required for the establishment of IC2 methylation, but that  KCNQ1  variants cause IC2 LOM only in a small number of BWS patients.

Frequency of KCNQ1 variants causing loss of methylation of Imprinting Centre 2 in Beckwith-Wiedemann syndrome