Expanding CEP290 mutational spectrum in ciliopathies.

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Ciliopathies are rare genetic disorders affecting multiple organs, often caused by mutations in genes related to primary cilia.
• The CEP290 gene is frequently implicated in ciliopathies such as Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome, and Leber congenital amaurosis (LCA).
• Some patients with these conditions present with only one detected CEP290 mutation, suggesting other genetic mechanisms may be involved.

Purpose of the Study:

• To investigate whether genomic rearrangements, specifically large deletions, in the CEP290 gene contribute to ciliopathies in patients with a single identified mutation.
• To expand the understanding of the mutational spectrum of the CEP290 gene in rare genetic disorders.

Main Methods:

• Exon dosage analysis was performed on genomic DNA from two groups of patients with CEP290 heterozygous mutations: five JSRD/MKS cases and four LCA cases.
• Analysis focused on identifying copy number alterations, including large deletions, within the CEP290 gene.

Main Results:

• A large heterozygous deletion in the C-terminus of the CEP290 gene was identified in one JSRD patient, leading to significantly reduced mRNA expression.
• No other copy number alterations were found in the remaining patients analyzed.
• This study identified multiexon deletions as a novel mechanism contributing to the CEP290 genotypic spectrum.

Conclusions:

• Multiexon deletions involving the CEP290 gene can cause ciliopathies.
• While not a frequent cause, screening for genomic rearrangements like deletions should be considered in patients with suspected CEP290-related disorders who have only one identified mutated allele.