NOTCH2 was first reported in relation to autosomal dominant Hajdu-Cheney syndrome-NOTCH2 in 2011 (Simpson et al., 2011 PMID: 21378985). This condition is characterized by acroosteolysis of distal phalanges and generalized osteoporosis, associated with additional ossification anomalies, craniofacial dysmorphism, dental anomalies and a wide range of other characteristics. Hearing loss, renal cysts, and cardiovascular anomalies are variably present. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and phenotypic variability. Therefore, NOTCH2 related phenotypes have been split into two disease entities, Alagille syndrome-NOTCH2 and Hajdu-Cheney syndrome-NOTCH2. Hajdu-Cheney syndrome-NOTCH2 has been lumped with serpentine fibula-polycystic kidney syndrome into a single entity, Hajdu-Cheney syndrome-NOTCH2, based on shared molecular mechanism and phenotypic spectrum. The split curation for autosomal dominant Alagille syndrome-NOTCH2 has been handled separately. Thirty-one variants (truncating variants in exon 34 that disrupt the PEST domain) that have been reported in 31 probands in nine publications (PMIDs: 21378985, 21378989, 39748536, 27312922, 36079132, 23401378, 21681853, 35289498, 21793104) in Hajdu-Cheney syndrome-NOTCH2 are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. The mechanism of pathogenicity is truncating variants in exon 34 which escape nonsense-mediated decay and disrupt the PEST domain (PMID: 21378985), which appear to act through a gain-of-function mechanism (PMID: 29149593). This gene-disease relationship is also supported by experimental evidence, including functional alterations in non-patient cells, altered expression in patient cells, and two mouse models (PMIDs: 39745791, 29149593, 20299358, 26627824). In summary, there is definitive evidence supporting the relationship between NOTCH2 and autosomal dominant Hajdu-Cheney syndrome-NOTCH2. 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 Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date April 14, 2025 (SOP Version 11).
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.