The relationship between KCNQ1 and autosomal recessive Jervell and Lange-Nielsen Syndrome (JLNS) was evaluated using the ClinGen Clinical Validity Framework as of 12/11/2017. Variants in KCNQ1 were first reported in humans with this disease as early as 1997 (Neyroud et al., PMID 9020846). At least 11 unique variants (missense, in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data knockout mouse models, rescue in mice, as well as expression of KCNQ1 in the heart and inner ear (PMIDs: 11226272, 11223304, 26084842, 9020846). The mechanism for disease is homozygous LOF of the KCNQ1 gene causes JLNS though alterations have also been shown to cause Romano-Ward Syndrome in an AD manner (PMID: 29037160). Variants in this gene have been reported in at least 9 probands in 9 publications (PMIDs 29037160, 27041150, 9020846, 27868350, 25187895, 24206879). Variants in this gene segregated with disease in 2 additional family members. In summary, KCNQ1 is definitively associated with Jervell and Lange-Nielsen Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.