ArticleEuropean journal of human genetics : EJHG2025
Pathogenic cryptic variants detectable through exome data reanalysis significantly increase the diagnostic yield in Joubert syndrome.
Article in European journal of human genetics : EJHG, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Systematic reanalysis of next-generation sequencing data in 101 neuromuscular disorder families enhances diagnostic yield, reveals intronic variants, and identifies a novel disease gene.Journal of neurology · 2026Article
- Clinical and functional characterization of a novel homozygous non-canonical splice mutation (c.1910-15_1910-11delinsTTACA) in CEP290 causing Joubert syndrome.Human genomics · 2026Article
- Exome Sequencing and MRI in Prenatal Diagnosis: A Case Report of Joubert Syndrome in Colombia.Case reports in genetics · 2026Article
- Further evidence ofJournal of medical genetics · 2025Article
- A CSPP1 variant associated with metabolic dysfunction in Joubert syndrome: a case report.Journal of medical case reports · 2025Article
- Neurodevelopmental Progression and Functional Outcomes in a Child With Joubert Syndrome: A Case Study.Cureus · 2025Article
- Phenotypic Spectrum ofGenes · 2025Review
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Authors and funding
26 authors.
Funding
Abstract
Joubert syndrome (JS) is a genetically heterogeneous neurodevelopmental ciliopathy. Despite exome sequencing (ES), several patients remain undiagnosed. This study aims to increase the diagnostic yield by uncovering cryptic variants through targeted ES reanalysis. We first focused on 26 patients in whom ES only disclosed heterozygous pathogenic coding variants in a JS gene. We reanalyzed raw ES data searching for copy number variants (CNVs) and intronic variants affecting splicing. We validated CNVs through real-time PCR or chromosomal microarray, and splicing variants through RT-PCR or minigenes. Cryptic variants were then searched in additional 44 ES-negative JS individuals. We identified cryptic "second hits" in 14 of 26 children (54%) and biallelic cryptic variants in 3 of 44 (7%), reaching a definite diagnosis in 17 of 70 (overall diagnostic gain 24%). We show that CNVs and intronic splicing variants are a common mutational mechanism in JS; more importantly, we demonstrate that a significant proportion of such variants can be disclosed simply through a focused reanalysis of available ES data, with a significantly increase of the diagnostic yield especially among patients previously found to carry heterozygous coding variants in the KIAA0586, CC2D2A and CPLANE1 genes.
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