Relevance. Kabuki Makeup Syndrome (KS) is a rare monogenic genetic disease characterized by multiple malformations. The phenotype includes specific facial features, skeletal and dermatoglyphic abnormalities, mental retardation, short stature. Most cases are associated with de novo mutations in the KMT2D and KMD6A genes. However, in 25% of patients with KS, the genetic basis remains unknown, which indicates the genetic heterogeneity of the disease and encourages further accumulation of clinical experience in KS. The article summarizes current data on the molecular geneticі aspects of the development of Kabuki Makeup Syndrome and describes its own clinical case of Kabuki Makeup Syndrome Type I.
Objective: to summarize the data on modern molecular-genetic aspects of the development of Kabuki makeup syndrome on the example of a clinical case.
Materials and methods. Analysis of scientific publications in the international electronic scientometric database Scopus, PubMed by keywords. Search depth – 15 years (2007-2021). The clinical case of Kabuki Makeup Syndrome from our own practice. Clinical and genealogical, molecular-genetic, cytogenetic, instrumental research methods.
Results. According to current data, the development of Kabuki Makeup Syndrome is due to mutations in the KMT2D (MLL2) gene, which belongs to the genes that control embryogenesis. KMT2D functions as a promoter of the expression of other genes and the KDM6A gene; encodes a large multidomain protein that interacts with the SET1/COMPASS complex. KDM6A is a cofactor physically associated with the KMT2D-COMPASS complex and exhibits demethylase activity in histone 3. Gene mutations KMT2D and KDM6A associated with KS lead to a lack of functioning of the corresponding enzyme, which leads to impaired methylation of histones and active genes in many organs and tissues of the body. Depending on the type of mutation in the KMT2D and KMD6A genes, there are two types of Kabuki Makeup Syndrome. KS type 1 with autosomal dominant type of inheritance due to pathogenic mutations in the KMT2D gene in a heterozygous state on chromosome 12q13.12. 70% of patients have KS1. Type 2 KS is an X-linked disease that develops as a result of a heterozygous pathogenic mutation in the KDM6 gene. In most cases, KS mutations are sporadic, but families with parent-to-child transmission have been described. In patients with phenotypic signs of KS pathogenic mutations are detected in 75% of cases. Pathogenic mutations in the KMT2D gene can be detected in mosaic form, and the carrier can pass this mutation on to offspring. Pathogenic mutations have not been described in phenotypically healthy people.
Here is our own observation. The girl with a combined congenital heart defect and multiple stigmas of dysembryogenesis was born at 36 weeks with a weight of 2930, 49 cm long, on the Apgar scale 8/8 points from the third planned pregnancy in parents who already had an older healthy boy. In connection with multiple malformations, the girl underwent a syndromic diagnosis using the program "Face2gene"; Kabuki Makeup Syndrome is suspected. Molecular genetic analysis revealed a pathogenic mutation (c.11884C>T) (p.Gln3962*) in the KMT2D gene, which is associated with autosomal dominant Kabuki Makeup Syndrome of type 1 (MedGen UID: 893727).
Conclusions. Kabuki Makeup Syndrome has clinical and molecular polymorphisms. Most of the registered KMT2D mutations occur de novo and occur in episodic cases. The described case demonstrates the molecular-positive Kabuki Makeup Syndrome of type I. The identified variant c.11884C>T(p.Gln3962*) in the KMT2D gene is associated with the autosomal dominant Kabuki Makeup Syndrome (MedGen UID: 893727). Verification of the diagnosis of the disease and prevention of KS in siblings is based on the results of molecular genetic analysis. The prognosis of this disease depends on the severity of heart disease and intellectual impairment. Early diagnosis determines the type and timing of therapeutic interventions, is crucial for medical and genetic counseling of the family.
A Novel GDAP1 Mutation 439delA is Associated with Autosomal Recessive CMT Disease
