Imprinting disorders

Gene: KCNQ1

I don't know

Proposed classification: Amber, pending further evidence.

The KCNQ1OT1:TSS DMR (imprinting control region 2; IC2) at 11p15.5 is located within KCNQ1 intron 10.

IC2 corresponds to the promoter of the long noncoding RNA KCNQ1OT1 and is methylated and inactive on the maternal chromosome. On the paternal chromosome, KCNQ1OT1 is transcribed and represses in cis the flanking imprinted genes, including the growth inhibitor CDKN1C, which is normally transcribed from the maternal allele. In 50% of the Beckwith-Wiedemann Syndrome (BWS) patients, loss of methylation (LOM) of IC2 leads to biallelic expression of KCNQ1OT1 and biallelic silencing of CDKN1C (PMID 30635621).

Pathogenic variants in KCNQ1 are associated with long-QT syndrome (LQTS) and can be inherited on the paternal or maternal allele.

Loss of methylation (LOM) of IC2 has been reported in a small number of individuals with KCNQ1 germline variants which additionally cause LQTS. Valente et al (PMID 30635621) reported three individuals with LQTS, features of BWS and LOM at IC2 and maternally inherited KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. Essinger et al (PMID 32393365) analysed KCNQ1 in 52 individuals with LOM at IC2 and identified one individual with a splice site variant causing premature transcription termination.

Microdeletions of IC2 variably involving KCNQ1, CDKN1C and KCNQ1OT1 on the maternal allele have been identified in a small number of patients with BWS. Maternally inherited LoF variants in CDKN1C are a known cause of BWS.

Beygo et al (PMID 30778172) demonstrated that disruption of KCNQ1 prevents methylation of IC2 supporting the hypothesis that transcription of KCNQ1 is required for establishing the maternal methylation imprint at IC2.
Sources: Literature

Created: 15 Oct 2021, 6:05 a.m. | Last Modified: 15 Oct 2021, 6:51 a.m.

Panel Version: 0.13

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)

Phenotypes
Beckwith-Wiedemann Syndrome

Publications

• PMID 30635621
• 32393365
• 30778172