CEP290

Inheritance Pattern: AR

Disease ID:MONDO:0100451

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0012432

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014442

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0014442

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100451

Submitter: ClinGen

The *CEP290* gene was first reported in relation to autosomal recessive ciliopathies in 3 publications in 2006. Sayer et al., 2006 (PMID: 16682973) reported *CEP290* variants in 7 families with Joubert syndrome and 1 with Senior-Loken syndrome; Valente et al., 2006 (PMID: 16682970) reported *CEP290* variants in 5 families with Joubert syndrome related disorders; and den Hollander et al., 2006 (PMID: 16909394) reported *CEP290* variants in 4 siblings with Leber congenital amaurosis. The *CEP290* gene has been associated with at least five conditions, Leber congenital amaurosis (MIM 611755), Bardet-Biedl syndrome (MIM 615991), Joubert syndrome (MIM 610188), Meckel syndrome (MIM 611134), and Senior-Loken syndrome (610189). The broad spectrum of disease can include retinal features such as severely reduced visual acuity, night blindness, peripheral visual field constriction, reduced rod and cone electroretingram responses, retinal pigment degeneration, macular atrophy, and/or nystagmus. Renal features can include cystic kidney disease sometimes characterized as juvenile nephronophthisis. Central nervous system features can include molar tooth sign, hypoplastic vermis, occipital encephalocele, Dandy Walker malformation, and/or developmental delay. A smaller number of studies indicate that the spectrum of phenotypes in some patients may include breathing difficulties (PMID: 27434533, PMID: 16682970) and recurrent but moderate inflammatory diseases of the upper and lower airways, with underlying defects in respiratory ciliary ultrastructure and beat frequency (PMID: 20805370). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. In addition, there are not clear genotype-phenotype correlations for *CEP290* conditions. For this curation, the disease entities have been lumped into one disease entity, *CEP290*-related ciliopathy (MONDO: 0100451). This curation includes 11 *CEP290* gene variants that have been reported in 19 probands in 6 publications (PMIDs: 17345604, 16909394, 24807808, 16682970, 16682973, 27434533). Multiple probands were found to have a deep intronic *CEP290* variant, c.2991+1655A>G, which is common among patients in the United States and Northwest Europe. This variant is commonly associated with non-syndromic retinal disease and has been shown to create cryptic exon and has been shown to result in mix of nonsense p.Cys998* and wild-type protein (PMID: 16909394). At least 300 variants have been reported in humans, including frameshift, nonsense, splice site, missense, and large deletions. The mechanism for disease is homozygous loss of function/reduced function. More evidence is available in the literature, but the maximum score for genetic evidence has already been reached. This gene-disease association is supported by animal models, expression studies, and *in vitro* functional assays. *CEP290* is expressed in the developing human kidney and brain (PMID: 23028714), the developing zebrafish cerebellum and retina (PMID: 16682973), and the mouse retina (PMID: 16632484). CEP290 has been shown *In vitro* to interact with RPGR, which is encoded by a gene associated with inherited retinal disease (PMID 16632484), and NPHP5/IQCB1, encoded by a gene associated with Senior-Loken syndrome/nephronophthisis (PMID: 18723859). A zebrafish morpholino knockdown resulted in a phenotype similar to Joubert syndrome with neurologic, ocular, and renal differences (PMID: 16682973). Furthermore, in human fibroblast cultures, CEP290 mutations have been shown to induce a ciliogenesis defect (PMID: 24807808). There are two naturally occurring animal models for *CEP290*-related disease, both exhibiting retinal phenotypes. The rd16 mouse is a naturally occurring mutant mouse with in-frame *CEP290* deletion. These mice exhibit early-onset retinal dystrophy with severely reduced electroretinogram and abnormal retinal histology (PMID 16632484, 17554762). There is also a lineage of cats, originally identified in Sweden, with late-onset recessive retinal degeneration that were found to have a *CEP290* intronic variant that creates canonical splice donor site and ultimately premature protein truncation (PMID: 17507457). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is Definitive evidence to support the relationship between *CEP290* and *CEP290*-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease clinical validity classification was approved by the Retina GCEP on February 3, 2022, with the ClinGen Motile Ciliopathy GCEP as secondary contributors (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0017842

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012723

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012432

Submitter: G2P