Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith–Wiedemann locus

Abstract

Purpose Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

Phenotype evolution and health issues of adults with Beckwith‐Wiedemann syndrome

“…Patient #31 (female) and #32 (male) were siblings. In their family segregates an intragenic inverted microduplication of 160‐kB within KCNQ1 exons 10 responsible for both Long QT syndrome type 1 (LQTS1) (Valente et al, ) and IC2‐LoM (Chiesa et al, ). They physiologically conceived and had children with unrelated partners.…”

Syndromic Disorders Caused by Disturbed Human Imprinting

“…Approximately 50% of cases are caused by LoM at IC2 (IC2-LoM) leading to reduced expression of CDKN1C, normally expressed by the maternal chromosome only. IC2-LoM is usually a sporadic primary epigenetic defect, however rare familial cases carrying genetic mutations causing secondary hypomethylation have been described (30). An increasingly growing fraction of patients with IC2-LoM also display methylation abnormalities at other imprinted loci leading to additional phenotypes (MLID) (31,32).…”

DNA Methylation in the Diagnosis of Monogenic Diseases

“…In addition, increased recurrence risk has been reported in cases with MLID with maternal-effect clinical SNVs (see ref [113] and MLID section). Moreover, high recurrence risk via maternal transmission has been described in rare cases of IC2 LOM with KCNQ1OT1 rearrangements or clinical SNVs [69]. Furthermore, a 50% recurrence risk is also present in the cases with clinical CDKN1C SNVs (only via maternal transmission), and in the cases of inherited chromosomal rearrangements (parental bias depends on the type of mutation).…”