Under the mask of Kabuki syndrome: Elucidation of genetic-and phenotypic heterogeneity in patients with Kabuki-like phenotype

Eur J Med Genet. 2018 Jun;61(6):315-321. doi: 10.1016/j.ejmg.2018.01.005. Epub 2018 Jan 4.


Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.

Keywords: EFTUD2; GRIN1; HUWE1; Intellectual disability; KMT2D; Kabuki syndrome.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 14
  • Comparative Genomic Hybridization
  • DNA-Binding Proteins / genetics
  • Exome
  • Face / abnormalities*
  • Face / physiopathology
  • Female
  • Genetic Heterogeneity*
  • Genotype*
  • Hematologic Diseases / diagnosis
  • Hematologic Diseases / genetics*
  • Hematologic Diseases / physiopathology
  • High-Throughput Nucleotide Sequencing
  • Histone Demethylases / genetics
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Mandibulofacial Dysostosis / genetics
  • Microcephaly / genetics
  • Neoplasm Proteins / genetics
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Peptide Elongation Factors / genetics
  • Phenotype*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Ribonucleoprotein, U5 Small Nuclear / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Vestibular Diseases / diagnosis
  • Vestibular Diseases / genetics*
  • Vestibular Diseases / physiopathology


  • DNA-Binding Proteins
  • EFTUD2 protein, human
  • GRIN1 protein, human
  • KMT2D protein, human
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptide Elongation Factors
  • Receptors, N-Methyl-D-Aspartate
  • Ribonucleoprotein, U5 Small Nuclear
  • Tumor Suppressor Proteins
  • Histone Demethylases
  • KDM6A protein, human
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases

Supplementary concepts

  • Kabuki syndrome