Submission Details

The CRB2 gene is located on chromosome 9 at q33.3 and encodes the crumbs cell polarity complex component 2 protein which plays a role in many cellular processes in early embryonic development, including: epithelial-to-mesenchymal transition at gastrulation, when mesodermal cells move inside the embryo; apical polarity complex maintenance in the cerebral cortex, in the retina and in photoreceptor polarity; and interacts with nephrin in slit diaphragm. CRB2 mutation was first reported in relation to familial idiopathic steroid resistant nephrotic syndrome (also known as focal segmental glomerulosclerosis 9; FSGS9) by Ebarasi (2015; PMID: 25557779) and with ventriculomegaly with cystic kidney disease by Slavotinek (2015, PMID: 25557780). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern and noted phenotypic overlap. Therefore, the following disease entities have been lumped into one disease entity, FSGS9 (OMIM:616220) and ventriculomegaly with cystic kidney disease (OMIM:219730). The preferred disease name suggested for this grouping of disorders is ‘Glomerulopathy, with or without ventriculomegaly and renal cysts - CRB2’. Many variants have been reported in CRB2 including mainly null variants, but also missense changes, and the maximum score for genetic evidence was reached (12 pts). The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by expression studies, protein interaction data, and a non-human model organism. In summary CRB2 is definitively associated with Glomerulopathy, with or without ventriculomegaly and renal cysts - CRB2. This has been demonstrated in both the research and clinical diagnostic setting, and has been upheld over time.