Heterozygous variants in DISP1 were first identified in two individuals with holoprosencephaly (HPE) like microform features in 2009 (PMID:19184110). In this initial publication, two nonsense variants were identified; while both probands were described as having cleft lip/palate, one proband was described as having seizures, developmental delay, and mild decortication, while the other was described as having hypotelorism and a single maxillary central incisor in the context of normal intelligence and a normal brain MRI. Both variants were inherited from reportedly unaffected parents. A mosaic de novo missense variant was later reported in a proband cleft lip/palate and congenital diaphragmatic hernia (CDH) (PMID:20799323), as well as a maternally inherited missense variant in a proband with lobar HPE (PMID:28640243). The mother of this proband was reportedly unaffected. Of note, DISP1 is not constrained for either missense or loss of function variants (gnomAD v.2.1.1). Given this and the relatively small number of reported heterozygous probands, a proposed disease mechanism could not be ascertained, making it difficult to assess the clinical relevance of the observed variants. For these reasons, each case was given a minimal number of points. In addition to the heterozygous cases, there have also reports of digenic inheritance in a fetus with cleft lip/palate (PMID:27363716) and in a family with variable features of HPE (PMID:26748417). There has also been a report of a proband with lobar HPE and biallelic variants in DISP1 (PMID:26748417). These probands were not included in this curation. Additional evidence is needed to understand the mechanisms by which variation in DISP1 may affect typical brain formation. Experimental evidence for this gene-disease relationship is minimal with expression studies in mouse embryo demonstrating high DISP1 expression in the developing mesenchyme of the diaphragm as well as in the early embryonic lung (PMID: 20799323). In summary, there is limited evidence to support a relationship between DISP1 and autosomal dominant HPE. This classification was approved by the ClinGen Brain Malformation GCEP on September 27, 2022 (SOP Version 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.