NEDD4L was first reported in relation to syndromic periventricular nodular heterotopia in 2016 (Broix et al., PMID 27694961). Evidence supporting this gene-disease relationship include case level data and experimental data. Variants in this gene have been reported in at least 15 probands in 5 publications, including at least 6 de novo missense variants (PMIDs: 27694961, 28515470, 30393983, 32117442, 34087865). To date, all reported cases have demonstrated periventricular nodular heterotopia and developmental delay; 13 of 15 probands demonstrated syndactyly, 8 demonstrated a cleft palate, and at least 5 demonstrated additional malformations of cortical development such as polymicrogyria. Recurrent variants are found in 11 of the reported cases (6 for one and 5 for the other). The mechanism of disease is dominant negative (PMID: 27694961). This gene-disease relationship is supported by animal models, in vitro studies of biochemical function, and cell culture assays using non-patient derived cells. More experimental evidence is available in the literature but not cited here, as a classification of definitive has been reached. In summary, NEDD4L is definitively associated with autosomal dominant periventricular nodular heterotopia 7. 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 Brain Malformations Gene Curation Expert Panel on 11/30/2021 (SOP Version 8).
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.