title: MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.
abstract: Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
authors: Departement of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
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authors: Makrythanasis
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authors: van Bon
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authors: Steehouwer
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authors: Rodríguez-Santiago
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authors: Simpson
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authors: Micale
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authors: Roscioli
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authors: Toledo
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authors: Vendrell
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authors: van der Burgt
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authors: van Lier
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authors: Reymond
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authors: Trembath
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authors: Perez-Jurado
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authors: Dupont
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authors: de Vries
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authors: Brunner
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authors: Veltman
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authors: Merla
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authors: Antonarakis
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authors: Hoischen
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006402:Hematologic Diseases / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D015837:Vestibular Diseases / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins
keywords: Kabuki syndrome; MLL2; Niikawa-Kuroki syndrome; genotype-phenotype correlation