From Genotype to Phenotype—A Review of Kabuki Syndrome

Abstract

Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa–Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype–phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines.

Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders

“…Our cohort includes six patients with Kabuki Syndrome due to pathogenic variants in KMT2D ( Supplementary table 1 ), which encodes a methyltransferase that regulates the expression of genes contributing to a diverse range of cellular functions. [61] The clinical phenotype of Kabuki Syndrome is unpredictable since some, but not all patients develop immune dysfunction that may include hypogammaglobulinemia and/or autoimmunity, such as vitiligo, autoimmune thyroiditis, myasthenia gravis, and immune cytopenias. [61] Of the six patients with Kabuki syndrome in our cohort, four had clinically detectable autoimmunity.…”

“…[61] The clinical phenotype of Kabuki Syndrome is unpredictable since some, but not all patients develop immune dysfunction that may include hypogammaglobulinemia and/or autoimmunity, such as vitiligo, autoimmune thyroiditis, myasthenia gravis, and immune cytopenias. [61] Of the six patients with Kabuki syndrome in our cohort, four had clinically detectable autoimmunity. Three of these had a positive composite measure due to increased cTfm1/17 percentages, cTfm17 percentages, and/or burden of high-titer IgG autoantibodies.…”

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system

“…EZH2 , EED2 , and SUZ12 mutations cause the neurodevelopmental disorders Weaver syndrome (OMIM #277590) ( 28 ), Cohen-Gibson syndrome (OMIM #617561) ( 30 ), and Imagawa-Matsumoto syndrome (OMIM #618786) ( 29 ). Mutations in EZH1 ( 27 ) and in KDM6B (OMIM #611577) ( 32 ) and KDM6A ( 31 ) (H3K27 demethylases) cause syndromic neurodevelopmental disorders and Kabuki syndrome (OMIM #147920 and #300867). Altered PRC activity is implicated in ataxia-telangiectasia ( 50 ) and Huntington’s disease ( 51 ).…”

Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1

“…The underlying heterogeneity of pathogenic variants in the KMT2D gene might partly explain the expansive phenotypic landscape of KS1 patients. Diverse variants of the same gene can alter distinct protein domains, which poses unique functional implications for the protein and may result in different clinical phenotypes (Banka et al, 2013; Barry et al, 2022; Cocciadiferro et al, 2018; Cuvertino et al, 2020; Schott et al, 2016). However, there is currently no clear correlation between a set of pathogenic variants in KMT2D and the resulting KS1 phenotype, meaning that a given variant may not lead to the same features in all patients.…”

“…However, molecular confirmation of KMT2D pathogenic variants is essential to distinguish KS1 from other similarly presenting developmental disorders, such as CHARGE syndrome (Kasdon & Fox, 2012). For a more comprehensive review of KS clinical features, see Adam et al, Dugan, and Barry et al (Adam et al, 2019; Barry et al, 2022; Dugan, 2021).…”