[Two novel and de novo KMT2D mutations on the same allele cause Kabuki syndrome].

Objective: To screen the candidate genes in a patient with Kabuki syndrome (KS), providing basis for genetic counseling, prenatal screening, prenatal diagnosis and facilitating early treatment. Methods: This study included a 16-year-old female KS patient born of non-consanguineous Chinese parents who presented to Department of Orthognathic & Cleft Lip and Palate Plastic Surgery, School and Hospital of Stomatology, Wuhan University. Genomic DNA was extracted from the peripheral blood of the subjects and analyzed by whole-exome sequencing (WES). Sanger sequencing was performed to validate the mutation in the candidate gene. The conformational and physicochemical changes of the mutant were analyzed by Alphafold2, Antheprot and DOG.2.0.1, respectively. Distribution of KMT2D mutations in patients with KS was analyzed based on the Human Gene Mutation Database Results: The proband manifested a typical KS facial gestalt, congenital cleft palate, fifth finger deformity, hypodontia, renal hypoplasia and hydronephrosis. Two de novo mutations c.[1166A>C; 1167dupC] (NM_003482) in cis on the same allele in the KMT2D gene were identified by WES and confirmed by allele-specific PCR. Bioinformatics analysis showed that three more α-helixes were added, and a (β-) turn and a (β-) sheet were reduced in KMT2D p. Y389S, p.V390Rfs*26 compared with the wild type. Meanwhile, the interceptive mutant-KMT2D protein p.V390Rfs*26 lost all four domains (FYRN domain, FYRC domain, SET domain, and PostSET domain), which may cause functional disabilities. Conclusions: Our study is the first to identify two novel and de novo KMT2D mutations in cis on the same allele in a KS patient and extends the KMT2D mutation spectrum of KS, providing evidence for genetic susceptibility counseling, prenatal screening and diagnosis, and early treatment of KS.