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CEP290 encodes a centrosomal protein critical for photoreceptor cilium formation and is the most frequently mutated gene in Leber congenital amaurosis type 10 (LCA10). Multiple large cohorts and familial segregation studies have firmly established a causal link between biallelic CEP290 variants and autosomal recessive LCA, with functional assays in cellular and animal models recapitulating the human phenotype. Given the reproducible identification of LoF and splice‐altering variants in unrelated probands and concordant experimental evidence, the gene–disease relationship is classified as Definitive.
ClinGen category: Definitive
Rationale: Over 120 unrelated probands with biallelic CEP290 variants including 16 homozygous or compound heterozygous cases in 76 unrelated patients ([PMID:16909394]) and 23 patients in a German cohort ([PMID:31734136]), multi-family segregation, concordant in vivo and in vitro functional data.
Inheritance is autosomal recessive. Segregation analysis across >16 families demonstrated co-segregation of biallelic CEP290 variants with disease in 19 additional affected relatives. A total of >200 probands have been reported, with variant classes including nonsense, frameshift, splice-site, and deep-intronic alleles. The intronic founder variant c.2991+1655A>G is present in ~21% of Quebec LCA patients ([PMID:16909394]) and accounts for 87% of German CEP290 cases ([PMID:31734136]). Additional recurrent and private truncating alleles (e.g., c.451C>T (p.Arg151Ter)) expand the allelic spectrum. Carrier frequency of c.2991+1655A>G reaches ~15% in north-western Europe.
Genetic evidence tier: Strong
Rationale: >120 AR LCA probands with biallelic LoF/splice variants; multiple unrelated families; founder and recurrent alleles; reached ClinGen genetic cap.
Loss of CEP290 disrupts ciliogenesis and photoreceptor outer segments. In zebrafish, cep290 knockdown impairs Kupffer’s vesicle size, melanosome transport, and visual behavior, all rescued by human N-terminal CEP290 fragment ([PMID:21257638]). Patient fibroblasts harboring c.2991+1655A>G show cryptic exon insertion and shortened primary cilia, both corrected by antisense oligonucleotides restoring wild-type splicing and ciliation ([PMID:27106101]). AAV-delivered miniCEP290580-1180 delays photoreceptor degeneration in rd16 mice, confirming domain-specific functional rescue.
Functional evidence tier: Strong
Rationale: Multiple in vivo (zebrafish, mouse) and in vitro (fibroblast, organoid) models demonstrating CEP290’s role in cilium formation, rescue by domain fragments or antisense oligonucleotides.
A humanized CEP290 mouse model exhibited unexpected cryptic exon usage differing from patients, indicating species-specific splice recognition and caution in murine modeling of deep-intronic variants ([PMID:24223178]).
Biallelic CEP290 truncating and deep-intronic splice variants cause early-onset severe retinal dystrophy by disrupting photoreceptor ciliogenesis. Genetic and experimental data converge on a loss-of-function mechanism amenable to splice modulation or mini-gene complementation. This has informed exon-skipping antisense oligonucleotide and AAV-based therapeutic approaches currently in clinical development. Key Take-home: Genetic testing for CEP290, especially the recurrent c.2991+1655A>G allele, guides diagnosis, prognostication, and eligibility for emerging gene-based therapies in LCA.
Gene–Disease AssociationDefinitiveOver 120 probands; multi-family segregation; concordant functional data Genetic EvidenceStrong
Functional EvidenceStrongIn vivo and in vitro models demonstrate CEP290’s role in ciliogenesis; rescue by domain fragments and AONs |