CD2AP

Inheritance Pattern: AR

Disease ID:MONDO:0011917

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005363

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011917

Submitter: ClinGen

The *CD2AP* gene is located on chromosome 6 at p12.3 and encodes the CD2 associated protein. *CD2AP* acts as a scaffolding protein that interacts with the cytoplasmic domain of nephrin in complex with podocin. Provides structure/regulation to the foot process of podocytes and the slit diaphragm (PMID: 11733557). In the kidney, *CD2AP* is primarily expressed in glomerular podocytes, and its absence results in improper formation of the slit diaphragm (PMID: 10514378) and the protein filtration barrier of the kidney (PMID: 16889564). 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 (FSGS) (OMIM:607832) and autosomal recessive FSGS (OMIM:607832). Autosomal dominant FSGS has been curated separately. *CD2AP* was first reported in relation to autosomal recessive FSGS in 2007 (Löwik et al., PMID: 17713465). FSGS is a pathologic entity associated clinically with proteinuria, nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (PMID: 16932363). The mechanism of pathogenicity is known to be loss of function. Four variants (nonsense and frameshift) have been reported in four probands in four publications (PMIDs: 17713465, 30348286, 30612599, 36964972) included in this curation. A total of 7.1/12 pts. for genetic evidence was reached considering case-level data. This gene-disease relationship is also supported by functional studies, expression studies, and animal models. One mouse model with homozygous knock-in of c.592_593insTCAC (p.Ser198IlefsTer3), which is also observed in a patient with FSGS, phenocopied FSGS (PMIDs: 30612599). Additionally, *CD2AP* expression is observed in the glomerular basement membrane and is required for proper formation of the slit diaphragm and the protein filtration barrier of the kidney (PMID: 10514378, 10997929, 16889564). A total of 5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CD2AP* and autosomal recessive focal segmental glomerulosclerosis. 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 Glomerulopathy GCEP on the meeting date April 8, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0011917

Submitter: Labcorp Genetics (formerly Invitae)