title: Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring.
abstract: Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: J
authors: J
authors: Paděrová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: A
authors: A
authors: Holubová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: M
authors: M
authors: Simandlová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: A
authors: A
authors: Puchmajerová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: M
authors: M
authors: Vlčková
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: M
authors: M
authors: Malíková
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: R
authors: R
authors: Pourová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: S
authors: S
authors: Vejvalková
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: M
authors: M
authors: Havlovicová
authors: Department of Medical Genetics, Charles University Prague-Faculty of Medicine and University Hospital Hradec Králové, Hradec Králové, Czech Republic.
authors: M
authors: M
authors: Šenkeříková
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: N
authors: N
authors: Ptáková
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: J
authors: J
authors: Drábová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: J
authors: J
authors: Geryk
authors: Department of Obstetrics & Gynecology, Centre for Mendelian Genomics, Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors: A
authors: A
authors: Maver
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: A
authors: A
authors: Křepelová
authors: Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors: M
authors: M
authors: Macek
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D018153:Czech Republic; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D015894:Genome, Human; D006402:Hematologic Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D015837:Vestibular Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human
keywords: KDM6A; KMT2D; Kabuki syndrome; MLL2; MLL2-Kabuki score; MLPA; Sanger DNA sequencing; array CGH; phenotyping