DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2D VUS and sensitivity in validating postzygotic mosaicism.
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:
25 Mar 2024
25 Mar 2024
Historique:
received:
23
11
2023
accepted:
13
03
2024
revised:
05
03
2024
medline:
26
3
2024
pubmed:
26
3
2024
entrez:
26
3
2024
Statut:
aheadofprint
Résumé
Autosomal dominant Kabuki syndrome (KS) is a rare multiple congenital anomalies/neurodevelopmental disorder caused by heterozygous inactivating variants or structural rearrangements of the lysine-specific methyltransferase 2D (KMT2D) gene. While it is often recognizable due to a distinctive gestalt, the disorder is clinically variable, and a phenotypic scoring system has been introduced to help clinicians to reach a clinical diagnosis. The phenotype, however, can be less pronounced in some patients, including those carrying postzygotic mutations. The full spectrum of pathogenic variation in KMT2D has not fully been characterized, which may hamper the clinical classification of a portion of these variants. DNA methylation (DNAm) profiling has successfully been used as a tool to classify variants in genes associated with several neurodevelopmental disorders, including KS. In this work, we applied a KS-specific DNAm signature in a cohort of 13 individuals with KMT2D VUS and clinical features suggestive or overlapping with KS. We succeeded in correctly classifying all the tested individuals, confirming diagnosis for three subjects and rejecting the pathogenic role of 10 VUS in the context of KS. In the latter group, exome sequencing allowed to identify the genetic cause underlying the disorder in three subjects. By testing five individuals with postzygotic pathogenic KMT2D variants, we also provide evidence that DNAm profiling has power to recognize pathogenic variants at different levels of mosaicism, identifying 15% as the minimum threshold for which DNAm profiling can be applied as an informative diagnostic tool in KS mosaics.
Identifiants
pubmed: 38528056
doi: 10.1038/s41431-024-01597-9
pii: 10.1038/s41431-024-01597-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : 5x1000_2019
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : RCR-2022-23682289
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : Current Research Funds
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : FOE_2020
Informations de copyright
© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.
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