ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-32158
• Date last evaluated: 2012-03-22
• Issue Type: ClinGen Gene Curation
• Gene type: ncRNA
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/10984
• OMIM: https://omim.org/entry/604115
• Gene Reviews: https://www.ncbi.nlm.nih.gov/books/NBK1394/?term=KCNQ1OT1

Location Information

• 11p15.5
• GRCh37/hg19 chr11: 2,629,558-2,721,228
• See linked regions:
• 11p15 region (includes H19, KCNQ1)

Evidence for Loss Phenotypes

• Loss of function score: 1
• Strength of Evidence: Little evidence for dosage pathogenicity
• Haploinsufficiency phenotype: BECKWITH-WIEDEMANN SYNDROME; BWS

Evidence for loss of function phenotype

PubMed ID	Description
15372379	Niemitz (2004): Authors describe a patient with Beckwith-Wiedemann syndrome with a maternally-inherited 250 kb deletion of KCNQ10T1. Reduced expression of CDKN1C was shown.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 2
• Strength of Evidence: Some evidence for dosage pathogenicity

Evidence for triplosensitivity phenotype

PubMed ID	Description
21920939	Chiesa (2012): Authors report a patient with Beckwith-Wiedemann syndrome with a maternally-inherited 160 kb duplication involving the imprinting control region 2 (the promoter of KCNQ10T1 - Smilinich, et al. PMID: 10393948), a portion of KCNQ1, and most of 5' KCNQ10T1. The imprinting control region 2 was hypomethylated and CDKN1C expression was reduced.
21780245	Demars (2011): Authors report a case of familial Beckwith-Wiedemann syndrome with a maternally-inherited 50 kb duplication involving two CpG islands in the imprinting control region 2, resulting in decreased CDKN1C expression and increased KCNQ10T1 expression.

• Triplosensitivity phenotype comment: The duplications described in Chiesa (2012) and Demars (2011) lead to aberrant methylation and decreased CDKN1C expression leading to BWS. However, it is not clear that all duplications of this gene would be functionally similar. Therefore, methylation testing of the ICR2 region and inheritance patterns would be necessary to establish a functional link between a duplication and the BWS phenotype.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.