ENTPD1 (Ectonucleoside triphosphate diphosphohydrolase-1, also known as CD39), hydrolyzes extracellular ATP and ADP to AMP, and plays an important role in regulating adenosine levels. ENTPD1 was first reported in relation to autosomal recessive complex hereditary spastic paraplegia in 2014 (Novarino et al., PMID: 24482476). A study describing a cohort of 27 individuals with homozygous variants in ENTPD1 identified common features of gait impairment, progressive spastic paraplegia and developmental delay/intellectual disability, with variable additional features (Calame et al. 2022, PMID: 35471564). Seven variants (missense, nonsense, frameshift) that have been reported in 12 affected individuals in 6 publications (PMIDs: 24482476, 29691679, 30652007, 33771085, 35758610, 35471564) are included in this curation. Additional evidence has been reported in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. In summary, there is definitive evidence to support the relationship between ENTPD1 and autosomal recessive complex hereditary spastic paraplegia. 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 Cerebral Palsy Gene Curation Expert Panel on April 6, 2023 (SOP 9).
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.