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

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

Author information

1
Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. Electronic address: Jana.Paderova@sinaihealthsystem.ca.
2
Department of Biology and Medical Genetics, Charles University Prague-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
3
Department of Medical Genetics, University Hospital Ostrava, Ostrava, Czech Republic.

Abstract

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

PMID:
29307790
DOI:
10.1016/j.ejmg.2018.01.005
[Indexed for MEDLINE]

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