CWC27

Inheritance Pattern: AR

Disease ID:MONDO:0009598

Submitter: ClinGen

*CWC27* was first reported in relation to retinitis pigmentosa with or without skeletal anomalies in 2017 (Xu et al., PMID: 28285769). Metaphyseal chondrodysplasia-retinitis pigmentosa syndrome is characterized by retinal degeneration (average onset of night blindness of 10 years of age, followed by restriction of visual fields), brachydactyly (affects primarily the distal phalanges), craniofacial abnormalities (include frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears), short stature, and neurologic defects. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, no differences were found in molecular mechanism (loss-of-function) and inheritance pattern (autosomal recessive) among the reported cases with or without skeletal features. As a result, diverse cases have been curated under the lumped disease term *CWC27*-related retinopathy with or without syndromic features. This curation includes ten variants (five nonsense, three frameshift, and two disrupting splicing) that have collectively been reported in ten probands in four publications (PMID: 28285769, PMID: 36718996, PMID: 31481716, PMID: 34828430). The variants segregated fully with disease, and were not found in the heterozygous state. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease association is also supported by experimental evidence. CWC27 encodes a member of the cyclophilin family of peptidyl-prolyl cis-trans isomerases. However, the N-terminal peptidyl-prolyl isomerase domain lacks catalytic activity due to its lack of a conserved active-site tryptophan, and is instead predicted to be a proline-binding protein. Three mouse models have been created; *Cwc27K338fs/K338fs* and two versions of *Cwc27* knockout, where all three models recapitulated the ocular phenotypes observed in human subjects (PMID: 28285769). The *Cwc27K338fs/K338fs* mouse, which carried the equivalent of the hypomorphic C-terminally truncating human allele p.Val335Serfs13, showed late onset ocular defects with no significant embryonic lethality compared to the more severe phenotype observed in the two *Cwc27* knockout mouse models (high embryonic lethality, growth retardation, ocular defects, and craniofacial/limb defects). The decreased severity of the phenotype may be explained by incomplete loss of expression of *Cwc27* (PMID: 28285769). In summary, *CWC27* is Definitively associated with *CWC27*-related retinopathy with or without syndromic features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 3rd, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0009598

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009598

Submitter: Labcorp Genetics (formerly Invitae)