PRG4

Inheritance Pattern: AR

Disease ID:MONDO:0008828

Submitter: Illumina

The PRG4 gene is located on chromosome 1 at 1q31.1 and encodes the proteoglycan 4 protein, which is lubricating component of the synovial fluid and acts as a boundary lubricant at the cartilage surface. It also has a chondroprotective feature and acts by preventing protein deposition from the synovial fluid onto the cartilage surface. PRG4 was first reported in relation to autosomal recessive, camptodactyly-arthropathy-coxa vara-pericarditis syndrome in 1999 (10545950: Marcelino et al. 1999). At least seven unique loss of function variants have been reported in literature. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least six probands from three publications (10545950: Marcelino et al. 1999; 27224999: Peters et al. 2016; 29397575: Yilmaz et al. 2018). Variants in this gene segregated with disease in three families. One of the families reported 12 affected family members, five of whom were genotyped. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Homozygous loss of function is implicated as the mechanism of disease. This gene-disease association is supported by expression studies and two independent Prg4 -/- mouse modes that recapitulate the human disease (10545950: Marcelino et al. 1999; 15719068: Rhee et al. 2005; 20191580: Coles et al. 2010). In summary, PRG4 is definitively associated with autosomal recessive, camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Inheritance Pattern: AR

Disease ID:MONDO:0008828

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008828

Submitter: ClinGen

The PRG4 gene is located on chromosome 1 at 1q31.1 and encodes the proteoglycan 4 protein, which is a lubricating component of synovial fluid and acts as a boundary lubricant at the cartilage surface. It also has a chondroprotective feature and acts by preventing protein deposition from the synovial fluid onto the cartilage surface. PRG4 was first reported in relation to autosomal recessive, camptodactyly-arthropathy-coxa vara-pericarditis syndrome in 1999 (Marcelino et al., 1999 PMID 10545950). This is a rare disorder characterized by early onset camptodactyly, non-inflammatory arthropathy with synovial hyperplasia, and progressive coxa vara deformity. Pericardial or pleural effusions have also been reported in some patients. Camptodactyly is usually the first finding in the majority of patients, followed by swellings of the wrists, knees, and elbows around the age of 4 years. Large joint involvement and age of onset of pain varies among patients. Severe hip and vertebral involvement developed after 20 years of age. At least 7 unique loss of function variants have been reported in literature. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 6 probands from 3 publications (Marcelino et al., 1999 PMID 10545950; Peters et al., 2016 PMID 27224999; Yilmaz et al., 2018 PMID 29397575). Variants in this gene segregated with disease in three families. One clan comprising five families reported 12 affected family members, five of whom were homozygous for the same variant (PMID 29397575). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by two independent Prg4 KO mouse modes that recapitulate the human disease (Rhee et al., 2005 PMID 15719068; Coles et al., 2010 PMID 20191580). In summary, there is definitive evidence to support the relationship between PRG4 and autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date April 27th, 2021 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0008828

Submitter: PanelApp Australia