Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms

Wang, Yi-Rou; Xu, Nai-Xin; Wang, Jian; Wang, Xiumin

doi:10.1007/s12519-019-00309-4

Cited by 45 publications

(27 citation statements)

References 61 publications

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“…Its pathogenic variant results in the interruption of histone methylation related to gene expression, thus affecting normal growth and development as well as many other processes described in other chapters. Its role in development, metabolism, cell differentiation and tumor suppression has been recently described [145]. Defective histone demethylation, as a result of a somatic variant, may dysregulate gene expression and predispose to cancer.…”

Section: Oncological Issues In Kabuki Syndromementioning

confidence: 99%

“…Defective histone demethylation, as a result of a somatic variant, may dysregulate gene expression and predispose to cancer. KMT2D has been defined as one of the most commonly mutated genes in a number of cancers such as gastric cancer, lymphoma and medulloblastoma [145]. The lung-specific loss of KMT2D promotes lung tumorigenesis and upregulates tumorigenic processes such as glycolysis in a recent mouse model [146].…”

Section: Oncological Issues In Kabuki Syndromementioning

confidence: 99%

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Kabuki Syndrome—Clinical Review with Molecular Aspects

Boniel

Sztefko

Śmigiel

et al. 2021

Genes

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Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

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Section: Oncological Issues In Kabuki Syndromementioning

confidence: 99%

Section: Oncological Issues In Kabuki Syndromementioning

confidence: 99%

Kabuki Syndrome—Clinical Review with Molecular Aspects

Boniel

Sztefko

Śmigiel

et al. 2021

Genes

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“…Pathogenic loss-of-function (lof) variants in the KMT2D gene with an autosomal dominant pattern of inheritance have been linked to the great majority of cases of Kabuki syndrome, which is one of the most well-characterized pediatric chromatinopathies [ 6 ] and is hallmarked by multiple congenital anomalies and intellectual disabilities [ 7 , 8 ]. A lower percentage of cases of Kabuki syndrome are related to pathogenic variants in the KDM6A gene, which encodes another important component of the ASCOM complex that is responsible for H3K27 demethylation of repressive polycomb-derived methylation marks [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration

Pacelli

Adipietro

Malerba

et al. 2020

Cells

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KMT2D encodes a methyltransferase responsible for histone 3 lysine 4 (H3K4) mono-/di-methylation, an epigenetic mark correlated with active transcription. Here, we tested the hypothesis that KMT2D pathogenic loss-of-function variants, which causes the Kabuki syndrome type 1, could affect the mitochondrial metabolic profile. By using Seahorse technology, we showed a significant reduction of the mitochondrial oxygen consumption rate as well as a reduction of the glycolytic flux in both Kmt2d knockout MEFs and skin fibroblasts of Kabuki patients harboring heterozygous KMT2D pathogenic variants. Mass-spectrometry analysis of intermediate metabolites confirmed alterations in the glycolytic and TCA cycle pathways. The observed metabolic phenotype was accompanied by a significant increase in the production of reactive oxygen species. Measurements of the specific activities of the mitochondrial respiratory chain complexes revealed significant inhibition of CI (NADH dehydrogenase) and CIV (cytochrome c oxidase); this result was further supported by a decrease in the protein content of both complexes. Finally, we unveiled an impaired oxidation of glucose and larger reliance on long-chain fatty acids oxidation. Altogether, our findings clearly indicate a rewiring of the mitochondrial metabolic phenotype in the KMT2D-null or loss-of-function context that might contribute to the development of Kabuki disease, and represents metabolic reprogramming as a potential new therapeutic approach.

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“…Three genetically diagnosed patients with SMCP had a heterozygous pathogenic variant of KMT2D. KS is difficult to diagnose in neonates and infants because their facial features are not as obvious as those of older children [ 3 ]. One of these patients (case 8), despite being diagnosed with KS in another hospital, was not suspected to have SMCP for delayed speech development.…”

Section: Discussionmentioning

confidence: 99%

“…A clinical diagnosis based on unique facial features, as reported by Niikawa and Kuroki, is the most commonly used diagnostic tool [ 2 ]. The facial features of patients with KS include long palpebral fissures with slight ectropion of the lateral third of the lower eyelid and sparse lateral eyebrows [ 3 ]. In addition, patients with KS show a variable range of abnormalities including mild mental retardation, hearing difficulty, cardiac anomaly, and skeletal instability.…”

Section: Introductionmentioning

confidence: 99%

Characteristics and surgical outcomes of cleft palate in kabuki syndrome: a case series of 11 patients

Kim

Kang

et al. 2021

BMC Pediatr

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Objective A significant number of patients with KS have cleft palate (CP) or submucous cleft palate (SMCP) and show delayed speech development. However, few reports have discussed the characteristics of CP in KS and the outcomes of postoperative speech development. The purpose of this study was to investigate the characteristics and surgical outcomes of CP in patients with KS, and to discuss the importance of the diagnosis of CP or SMCP. Methods We conducted a retrospective study on patients with clinically diagnosed KS who underwent palatoplasty. Clinical and surgical data were collected from patients’ medical records, and velopharyngeal function was evaluated using nasopharyngoscopy and speech analysis. Results In 11 cases, 5 patients had CP (45.5%) and 6 had SMCP (54.5%). Four patients who were genetically tested had a pathogenic variant of KMT2D. Seven of nine patients (77.8%) who underwent conventional palatoplasty showed velopharyngeal insufficiency and hypernasality. All patients who underwent pharyngeal flap surgery achieved velopharyngeal competency. Statistical analysis revealed a statistically significant difference in postoperative results between non-syndromic and KS patients. Conclusion Patients with SMCP may be more common than previously reported. The results showed that it is difficult to produce optimal results with conventional palatoplasty; therefore, pharyngeal flap surgery should be considered as a treatment to obtain favorable results. Pharyngeal flap surgery in patients with KS should be carefully designed based on speech evaluation and nasopharyngoscopic findings.

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Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms

Cited by 45 publications

References 61 publications

Kabuki Syndrome—Clinical Review with Molecular Aspects

Kabuki Syndrome—Clinical Review with Molecular Aspects

Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration

Characteristics and surgical outcomes of cleft palate in kabuki syndrome: a case series of 11 patients

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