Pathogenic cryptic variants detectable through exome data reanalysis significantly increase the diagnostic yield in Joubert syndrome.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
11 Oct 2024
11 Oct 2024
Historique:
received:
27
05
2024
accepted:
25
09
2024
revised:
02
09
2024
medline:
12
10
2024
pubmed:
12
10
2024
entrez:
11
10
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 39394465
doi: 10.1038/s41431-024-01703-x
pii: 10.1038/s41431-024-01703-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondazione Telethon (Telethon Foundation)
ID : GGP20070
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : Ricerca Finalizzata RF-2019-12369368
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RC 2023 line 1
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : MNESYS (PE0000006)
Informations de copyright
© 2024. The Author(s).
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