Submission Details

CFAP418 (previously known as C8orf37) was first reported in relation to autosomal recessive Bardet Biedl syndrome in 2012 (Estrada-Cuzcano et al., PMID: 22177090). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. Additional families have affected members diagnosed with conditions such as retinitis pigmentosa or cone-rod dystrophy (PMID: 22177090, PMID: 25802487). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic CFAP418 disruption) were found to be consistent among patients diagnosed with Bardet-Biedl syndrome 21 (MIM# 617406), cone-rod dystrophy 16 (MIM# 614500), or retinitis pigmentosa 64 (MIM# 614500). The phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic CFAP418 variants have been lumped into a single disease entity, referred to as CFAP418-related ciliopathy.

This curation includes eight variants (three canonical splicing, two missense, and three nonsense) that have been reported in nine probands in five publications (PMIDs: 22177090, 25802487, 27008867, 26854863, 26865426). The mechanism of pathogenicity is likely to be biallelic loss-of-function.

This gene-disease association is also supported by an expression study showing that CFAP418 is highly expressed in the retina, as well as localized at base of the photoreceptor connecting cilia and photoreceptor inner segments (PMID: 22177090). Using a zebrafish model with knockdown of the CFAP418 ortholog, Heon et. al. show that the Kuppfer’s vesicle (a ciliated organ) of mutant zebrafish is smaller and has reduced cilia content compared to wild-type fish. Overexpressing the p.Arg177Trp or p.Gln182Arg variants in CFAP418 results in Kuppfer’s vesicle defects and visual impairment (PMID: 27008867). Finally, a CFAP418 knockout mouse model shows reduced scotopic and photopic ERG responses, progressive retinal degeneration, and a reduction in outer segment protein expression in the retina (PMID: 29440555).

In summary, CFAP418 is definitively associated with autosomal recessive CFAP418-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 11, 2024 (SOP Version 10).