Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature

Kabuki syndrome type 1 (KS1) is a monogenic disorder arising from pathogenic variants within KMT2D and characterized by syndromic neurodevelopmental delay. We report the retrospective identification of a causative AluY insertion within KMT2D in a genetically unsolved individual with typical KS1 features, after identification of a DNA methylation signature. This is the first documentation of Alu insertion as a molecular mechanism responsible for KS1. This study emphasizes the need for reanalyzing inconclusive sequencing data in individuals with gene-specific phenotypes and reinforces episignature as a reliable diagnostic tool when NGS approaches fail to provide conclusive results in individuals with rare diseases.

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Journal
Clinical Epigenetics
Published
2025-04-29
DOI
https://doi.org/10.1186/s13148-025-01879-z
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature

Thomas Guignard, Nathalie Ruiz-Pallares, Mouna Barat‐Houari, Claire Jeandel et al.
Clinical Epigenetics
Genomics and Rare Diseases
article

Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature

Thomas Guignard, Nathalie Ruiz-Pallares, Mouna Barat‐Houari, Claire Jeandel, Jacques Puechberty, Jennifer Kerkhof, Pascal Pujol, Bekim Sadiković, Quentin Sabbagh, Cassandra Rastin, David Geneviève, Fanny Merklen
article en

Abstract

Kabuki syndrome type 1 (KS1) is a monogenic disorder arising from pathogenic variants within KMT2D and characterized by syndromic neurodevelopmental delay. We report the retrospective identification of a causative AluY insertion within KMT2D in a genetically unsolved individual with typical KS1 features, after identification of a DNA methylation signature. This is the first documentation of Alu insertion as a molecular mechanism responsible for KS1. This study emphasizes the need for reanalyzing inconclusive sequencing data in individuals with gene-specific phenotypes and reinforces episignature as a reliable diagnostic tool when NGS approaches fail to provide conclusive results in individuals with rare diseases.

Clinical EpigeneticsVol. 17(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), London Health Sciences Centre (CA), Centre Hospitalier Universitaire de Montpellier (FR), Institute of Predictive and Personalized Medicine of Cancer (ES), Institut de Recherche pour le Développement (FR)
Genome Canada
Openalex Percentile: Top 89%
Genomics and Rare Diseases
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Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature — Thomas Guignard, Nathalie Ruiz-Pallares, et al. · Clinical Epigenetics (2025) | TGRS Research Map | TGRS