The CD2AP gene is located on chromosome 6 at p12.3 and encodes the CD2 associated protein. CD2AP is expressed in the kidney and it provides structure to the foot process of podocytes and the slit diaphragm (PMID: 11733557).
Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant focal segmental glomerulosclerosis (OMIM: 607832) and autosomal recessive focal segmental glomerulosclerosis (OMIM: 607832).
The preferred disease name suggested for this grouping of disorders is focal segmental glomerulosclerosis (FSGS).
CD2AP was first reported in relation to autosomal dominant focal segmental glomerulosclerosis in 2003 (Kim et al., PMID: 12764198). Clinical manifestation involves proteinuria, nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (Meyrier, 2005). The mechanism of pathogenicity is known to be loss of function.
Two variants (frameshift and a large intronic deletion involving a canonical splice site) have been reported in 2/2 probands 2/2 publications (PMIDs: 12764198, 34408996 included in this curation). A total of 3/12 pts. for genetic evidence was reached.
This gene-disease relationship is also supported by expression studies, animal models, and rescue assays. CD2AP is expressed in developing podocytes and the glomerular basement membrane (PMID: 10997929). Additionally, variation in CD2AP has been shown to result in the improper formation of the slit diaphragm and the protein filtration barrier of the kidney (PMIDs: 10514378, 16889564). One mouse model demonstrated that mice heterozygous for altered CD2AP presented glomerular lesions similar to FSGS in humans (PMID: 12764198). The homozygous mice died of proteinuria. A second study of the same mouse model demonstrated that podocyte-specific expression of CD2AP rescued the renal defects of the CD2AP-deficient mice (PMID: 15951437). A total of 5/6 pts. for experimental evidence was reached.
In summary, there is moderate evidence supporting the relationship between CD2AP and autosomal dominant FSGS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings.
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