Welcome to the CEP290 mutation database! This database has been designed to provide up-to-date information about genetic variation of the CEP290 gene in different associated phenotypes (OMIM 610142). The site was launched in 2009 as a locus-specific database following the guidelines of the Human Genome Variation Society (HGVS) (NM_025114). So far, the CEP290 mutation database contains 113 unique mutations identified in 198 probands (last update: october 2009).

CEP290 is one of the finest examples of genes in which mutations may cause a wide variety of phenotypes, ranging from the lethal Meckel syndrome over syndromic Joubert syndrome to isolated retinal dystrophy. Given its expression in ciliary centrosomes, mutations may affect the structure and function of cilia throughout the whole body, thereby causing this spectrum of ciliopathies.

At the moment, it is still not clear exactly which events define the associated phenotype. Recent studies on ciliary proteins have nicely shown the importance of modifier alleles in influencing phenotypes (Leitch et al. and Khanna et al.). These findings are only the tip of the iceberg; identification of additional variants in other components of the ciliary proteome in combination with the knowledge of their mutual interactions, will further clarify the broad phenotypic spectrum of these ciliopathies. In addition, certain (type of) mutations may differently affect the expression or behavior of CEP290. An example of this is the c.2991+1655A>G mutation which has so far only been seen in patients with isolated Leber congenital amaurosis (den Hollander et al. and Perrault et al.).

The goal of this database is to provide detailed information not only about the variants itself, but also concerning the phenotype of the individuals carrying these variants. In addition to the description of certain symptoms, a disease has been assigned to each patient. This disease calling is based on a classification developed by Valente and coworkers in which a clear distinction is made between the affection of different organ systems (Valente et al.). It is important to note that these phenotypes might be incomplete since a number of patients were too young at the time of investigation to show certain clinical signs as for example renal insufficiency.

Information on variants can be retrieved using the Overview page or the Mutation Browser.

The Overview contains all unique variants, with their occurrence and links to dbSNP, UniProt and OMIM. Selecting a variant will lead you to the variant-specific page, on which you will find information about the functional effect of the variant, and a list of all patients that carry this mutation. Mutation nomenclature is based on the NCBI RefSeq NM_025114, according to HGVS guidelines.

Variant-specific information depends on the nature of the variant, but always includes the protein domain (Sayer et al.) and frequency in control individuals (if tested). In the case of nonsense and truncating mutations, it is indicated whether mRNA might be subjected to nonsense mediated decay (NMD) (Nagy et al.). For missense mutations, we provide the Grantham score (Grantham et al.), and links to the SIFT and PolyPhen sites. For both these prediction tools, the parameters are automatically filled in, using respectively the GI number (109255233) and UniProt ID (O15078) of CEP290. Splice-site mutations contain links to the splice site prediction programs NetGene2 and Berkeley Drosophila Genome Project (BDGP).

The patient list gives an overview of all patients in which the selected mutation was found. If available, specific information is provided regarding disease, gender, age, origin, segregation and parental consanguinity. Importantly, mutations on both alleles are displayed using the nomenclature of the concerning publication, giving you the opportunity to easily retrieve the specific variant in the publication. Selecting the mutation on the second allele, will guide you to its variant-specific page. Phenotypic information will appear by selecting the patients ID, and consists of ocular, renal, neurological and other signs.

Using the Mutation Browser, one can execute queries by defining (a combination of) parameters. These parameters can be set in either a quick or advanced search.

The quick search requires that you know specific information about variants (HGVS nucleotide or protein nomenclature) or patients (patient of family ID). The advanced search consists of three sections: variant, patient and source information. In and between these sections, different parameters can be set. One can select different values for one parameter using the control button (eg search for mutations in patients with SLS and JS). In addition, different parameters can be combined in one search (eg search for mutations in patients with SLS and JS and located in the CCI domain).

For the output, two options are possible: a list of mutations (“search mutation(s)”) or a list of patients (“search patient(s)”) which meet all the requirements of the query. The format of these lists corresponds to respectively the mutation overview or the patient list provided in the variant-specific pages, with the latter containing the HGVS nomenclature of the variants, instead of the nomenclature of the original paper. From the mutation list, one can easily extract an overview of all patients carrying the mutations resulting from the query.

Last but not least, users are highly encouraged to submit new or known variants they have identified. This is possible through the Submission page, on which one can enter information regarding the variant, the identification method and the patient.