Kabuki Syndrome Research Articles

Extremely Low Birth Weight Infant (Gestational Age of 29 Weeks) With Kabuki Syndrome Type I: Case Report and Literature Review.

This paper aimed to investigate the clinical phenotype of Kabuki syndrome (KS) in premature infants. This paper presents a case of an extremely low birth weight infant (gestational age 29 weeks) with KS1 caused by a variant in the KMT2D gene. The clinical, pathological, and differential diagnostic findings were comprehensively analyzed. A thorough literature review was also performed to enhance the understanding of KS, revealing its unique features and prognostic significance. The infant was a male with a gestational age of 29 weeks and a birth weight of 850 g. He had intrauterine growth retardation, characterized by cleft palate, sacrococcygeal skin depressions, and recurrent metabolic acidosis. Whole-exome sequencing revealed the c.4267C > T (p.Arg1423Cys) variant in the KMT2D gene, which was absent in his parents. The patient was discharged after 67 days of treatment, and he was followed up to 19 months of corrected gestational age, with growth retardation and expression language delay. Ten previous studies on preterm infants were retrieved, with 10 preterm infants. They all had characteristic facial features, such as long blepharophimosis, sparse and lateral 1/3 eyebrows, and large and prominent/cupped ears. Other manifestations were extrauterine growth delay (7/10), abnormal development of the cardiovascular system (7/10), abnormal development of the nervous system (5/10), and cleft palate (2/10). Kabuki syndrome is a rare hereditary disorder involving multiple organs and systems. Genetic assessment for preterm infants with congenital abnormalities is recommended.

Surgical management of congenital mitral stenosis in a patient with Kabuki syndrome.

Congenital mitral stenosis is a rare anomaly. We report successful surgical management of congenital mitral stenosis in a patient with Kabuki syndrome. A 15-month-old male with Kabuki syndrome was referred and echocardiography showed isolated congenital mitral stenosis. The valve was not repairable as it was showing severe stenotic features in multilevel fashion. Valve was replaced with mechanical valve. Postoperative course was uneventful without any rhythm problem and he has been doing well clinically during the 25 months follow-up with regular international normalized ratio checks.

Abnormal Immune Profile in Individuals with Kabuki Syndrome.

To analyze the lymphocyte subsets in individuals with Kabuki syndrome for better characterizing the immunological phenotype of this rare congenital disorder. We characterized the immunological profile including B-, T- and natural killer-cell subsets in a series (N = 18) of individuals with Kabuki syndrome. All 18 individuals underwent genetic analysis: 15 had a variant in KMT2D and 3 a variant in KDM6A. Eleven of the 18 individuals (61%) had recurrent infections and 9 (50%) respiratory infections. Three (17%) had autoimmune diseases. On immunological analysis, 6 (33%) had CD4 T-cell lymphopenia, which was preferentially associated with the KMT2D truncating variant (5/9 individuals). Eight of 18 individuals (44%) had a humoral deficiency and eight (44%) had B lymphopenia. We found abnormal distributions of T-cell subsets, especially a frequent decrease in recent thymic emigrant CD4 + naive T-cell count in 13/16 individuals (81%). The immunological features of Kabuki syndrome showed variable immune disorders with CD4 + T-cell deficiency in one third of cases, which had not been previously reported. In particular, we found a reduction in recent thymic emigrant naïve CD4 + T-cell count in 13 of 16 individuals, representing a novel finding that had not previously been reported.

Clinical and molecular characteristics of Korean patients with Kabuki syndrome.

Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. This study enhances the understanding of the clinical and genetic characteristics of KS.

Mll4 regulates tooth enamel development.

Amelogenesis, or enamel development, is a highly regulated process that leads to the formation of tooth enamel, which is critical for protecting teeth from decay and wear. Disruptions in the amelogenesis process can result in amelogenesis imperfecta, a group of genetic conditions characterized by inadequately formed enamel. This condition can include enamel hypoplasia, marked by thinning or underdevelopment of the enamel layer. Mutations in the MLL4 ( KMT2D ) gene, which encodes a histone H3-lysine 4-methyltransferase, are associated with Kabuki syndrome, a developmental disorder that can involve dental anomalies such as enamel hypoplasia. However, the specific role of MLL4 in amelogenesis and its underlying mechanisms remain poorly understood. To investigate the role of Mll4 in amelogenesis, we generated a conditional knockout mouse line with an ectoderm-specific deletion of Mll4 ( Krt14-Cre;Mll4 fl/fl , or Mll4 -cKO) and examined the gross, radiographic, histological, cellular, and molecular features in these mice. Micro-computed tomography and scanning electron microscopy analyses revealed that adult Mll4 -cKO mice exhibited 100% penetrant amelogenesis imperfecta, characterized by hypoplastic and hypomineralized enamel, partially phenocopying human Kabuki syndrome. Additionally, Mll4 -cKO neonates developed molar tooth germs with minor cusp shape alterations and mild delays in ameloblast differentiation at birth. RNA-seq analysis of the first molar tooth germ at birth revealed that approximately 33.7% of known amelogenesis-related genes were significantly downregulated in the Mll4 -cKO teeth. Intersection with Mll4 CUT&RUN-seq results identified 8 overlapping genes directly targeted by Mll4. Re-analysis of a single-cell RNA-seq dataset in the developing mouse incisor teeth revealed distinct roles for these genes in Mll4-regulated differentiation across various cell subtypes within the dental epithelium. Among these genes, Satb1 and Sp6 are likely directly targeted by Mll4 during the differentiation of pre-ameloblasts into ameloblasts. Taken together, we propose that Mll4 plays a crucial role in amelogenesis by directly activating key genes involved in ameloblast differentiation.

Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome.

Kabuki syndrome (KS) is a rare genetic disorder characterized by distinct facial features, intellectual disability, and multiple congenital anomalies. We conducted a comprehensive analysis of the genetic and phenotypic spectrum of KS in a Taiwanese patient group of 23 patients. KMT2D variants were found in 22 individuals, with missense (26.1%), nonsense (21.7%), and frameshift (17.4%) variants being the most prevalent. One patient had a KMT2D variant of uncertain significance. The most common clinical characteristics included distinct facial features (100%), intellectual disability (100%), developmental delay (95.7%), speech delay (78.3%), hypotonia (69.6%), congenital heart abnormalities (69.6%), and recurrent infections (65.2%). Other abnormalities included hearing loss (39.1%), seizures (26.1%), cleft palate (26.1%), and renal anomalies (21.7%). This study broadens the mutational and phenotypic spectrum of KS in the Taiwanese population, highlighting the importance of comprehensive genetic testing and multidisciplinary clinical evaluations for diagnosis and treatment.

Jaw-winking phenomenon in a diabetic patient with Kabuki syndrome.

Jaw-winking phenomenon in a diabetic patient with Kabuki syndrome.

Congenital hyperinsulinism and novel KDM6A duplications -resolving pathogenicity with genome and epigenetic analyses.

Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile -an episignature. We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing. Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature. WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3. Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS's in the KDM6A gene.

Clinical and molecular characteristics of Kabuki syndrome patients with missense variants-novel features and literature review.

Kabuki Syndrome (KS) encompasses a spectrum of clinical manifestations, primarily attributed to pathogenic variants in the KMT2D gene. This study aims to elucidate novel features in KS patients with missense variants, contrasting their presentation with both literature-reported cases of patients with missense pathogenic variants as well as other KS patients with truncating pathogenic variants. Employing a survey questionnaire and clinical evaluations, we examined ten KS patients with missense variants, focusing on their dysmorphism characteristics, behavior and psychomotor development. We identified unique features in missense variant patients, including foot hyperesthesia, musicality, and sensory integration disorders. Notably, despite similarities in developmental trajectories, distinct phenotypic traits emerged in missense variant cases, suggesting a potential genotype-phenotype correlation. These findings contribute to a deeper understanding of KS heterogeneity and underscore the importance of genotype-specific characterization for prognostic and therapeutic considerations. Further exploration of genotype-phenotype relationships promises to refine clinical management strategies and enhance patient outcomes in this complex syndrome.

Mll4 regulates postnatal palate growth and midpalatal suture development.

MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator during various organogenesis programs. Mutations in the MLL4 gene are the major cause for Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. The purpose of this study was to investigate the role of Mll4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. By using micro-computed tomography (CT), histology, cell mechanism assays, and gene expression analysis approaches, we examined the development and growth of the palate in the Mll4 -cKO mice. Gross intra-oral examination at adult stages showed that Mll4 -cKO mice had defects along the midline of the palate, which included disrupted rugae pattern and widened midpalatal suture. Micro-CT-based skeletal analysis in the adult mice revealed that the overall palate width was decreased in the Mll4 -cKO mice. By using whole-mount and histological staining approaches at perinatal stages, we identified that the midline defects started to appear as early as 1 day prior to birth, manifesting initially as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme cells. Genome-wide analysis of mRNA expression in the midpalatal suture tissue showed that Mll4 is essential for timely expression of major genes for cartilage development, such as Col2a1 and Acan , at birth. These results were validated through immunofluorescence staining, confirming that the expression of chondrogenic markers Sox9 and Col2a1 were markedly decreased, whereas that of the osteogenic marker Runx2 remained unchanged, in the midpalatal suture of the Mll4 -cKO mice. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in the Mll4 -cKO mice. In parallel, time-course micro-CT analysis during postnatal palatogenesis confirmed a transverse growth deficit in the palate of the Mll4 -cKO mice. Taken together, our results show that Mll4 is essential for timely occurrence of key cellular and molecular events that lead to proper midpalatal suture development and palate growth.

The significance of follow-up in patients with dysmorphic features: a case from clinical practice

Background. Kabuki syndrome is a rare disorder, that is characterized by typical facial dysmorphism, hypotonia, delay in intellectual and motor development. Case report. We present a case of a girl in whom polycystic left kidney was prenatally established. Born prematurely in 37 weeks by C section due to oligohydramnios. After birth, atresia of the anus with fistula, cysts in the left and reduced dimensions of the right kidney, were further established. A normal female karyotype was found and targeted sequencing analysis was conducted on a panel of 81 genes associated with renal abnormalities – no pathogenic variants were detected. The child was then followed up by its general practitioner. At the age of 2 years, she was again referred for genetic counseling, which revealed the following dysmorphic signs – long eye palpebral fissuras with ectropion of the lower eyelid, sparsed lateral eyebrows, depression of the nasal bridge, brachydactyly and others characteristic of Kabuki’s syndrome. The conducted molecular genetic analysis confirmed the clinical diagnosis – a likely pathogenic variant in the KMT2D gene was established. Conclusions. Certain pathognomonic facial may not present at birth and only appear after a few years. Therefore, monitoring of the evolution of dysmorphic traits is required.

Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1.

Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

Nonimmune Hydrops and Left-Sided Cardiac Defect: Prenatal Presentation of Kabuki Syndrome.

Nonimmune Hydrops and Left-Sided Cardiac Defect: Prenatal Presentation of Kabuki Syndrome.

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome.

Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). To characterize the clinical and molecular features of HI in children with KS. Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia. Thirty-three children with KS and HI. HI presentation, treatment, course, and genotype. Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D, 5 children (15%) had a pathogenic variant in KDM6A, and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years). Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.

Clinical and genetic characteristics of four children with Kabuki syndrome due to de novo variants of KMT2D gene

To explore the clinical and genetic characteristics of four children with Kabuki syndrome (KS) due to variants of KMT2D gene. Four children with KS diagnosed at the Children's Hospital of Shanxi Province between January 2020 and December 2022 were selected as the study subjects. Whole exome sequencing was carried out for the children and their family members. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. The KS phenotype scores for the four children were 7, 8, 6, and 6, respectively. Child 2 also presented with a rare solitary kidney malformation. Genetic testing revealed that all children had harbored novel de novo variants of the KMT2D gene, including c.16472_16473del, c.858dup, c.11899C>T, and c.12844C>T, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were classified as pathogenic. For children showing phenotypes such as distinctive facial features, intellectual disability, developmental delay, cardiac abnormalities, and urinary system anomalies, KS should be considered. Early diagnosis and intervention can be achieved through genetic testing, especially in the presence of KMT2D gene mutations.

KMT2D regulates activation, localization, and integrin expression by T-cells.

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice.

Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically shows phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption-the root of the pathogenesis-is similar in the different disease-relevant cell types. This is possible in principle, because all these cell types are subject to effects from the same causative gene, which has the same kind of function (e.g., methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2 and find that the chromatin accessibility changes in neurons are mostly distinct from changes in B or T cells. This is not because the neuronal accessibility changes occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that regulatory elements disrupted in B/T cells do show chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we are able to identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators and suggest that blood-derived episignatures, although useful diagnostically, may not be well suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

Prenatal diagnosis of Kabuki syndrome: A case report

Prenatal diagnosis of Kabuki syndrome: A case report

A Kabuki syndrome presenting with strabismus: case report

Kabuki syndrome affects many systems and is characterized by a typical facial appearance and is a genetically inherited disease. Ophthalmological involvement is quite common and can be diagnostic. In this article, we aimed to present the ophthalmological findings of our patient with Kabuki syndrome, who was diagnosed and treated based on ophthalmological findings.

Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet).

Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients(18%). Elevated CD3 + TCRαβ + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαβ + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.