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

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

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...

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Main Authors: Quentin Sabbagh, Nathalie Ruiz-Pallares, Cassandra Rastin, Jacques Puechberty, Thomas Guignard, Claire Jeandel, Fanny Merklen, Pascal Pujol, Jennifer Kerkhof, Bekim Sadikovic, Mouna Barat-Houari, David Geneviève
Format: Article
Language:English
Published: BMC 2025-04-01
Series:Clinical Epigenetics
Subjects:
Kabuki syndrome
KMT2D
Epigenetic signature
Alu element
Mobile element insertion
Online Access:https://doi.org/10.1186/s13148-025-01879-z
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Summary: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.
ISSN:1868-7083

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