Prenatal ultrasound and genetic characteristics of fetuses with Kabuki syndrome: A report of six cases and literature review

Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

Clinical and molecular analysis of Guangxi patients with Kabuki syndrome and KMT2D mutations

We aim to assess if genotype-phenotype correlations are present within ocular manifestations of Kabuki syndrome (KS) among a large multicenter cohort.We conducted a retrospective, medical record review including clinical history and comprehensive ophthalmological examinations of a total of 47 individuals with molecularly confirmed KS and ocular manifestations at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. We assessed information regarding ocular structural, functional, and adnexal elements as well as pertinent associated phenotypic features associated with KS. For both type 1 KS (KS1) and type 2 KS (KS2), we observed more severe eye pathology in nonsense variants towards the C-terminus of each gene, KMT2D and KDM6A, respectively. Furthermore, frameshift variants appeared to be not associated with structural ocular elements. Between both types of KS, ocular structural elements were more frequently identified in KS1 compared with KS2, which only involved the optic disc in our cohort. These results reinforce the need for a comprehensive ophthalmologic exam upon diagnosis of KS and regular follow-up exams. The specific genotype may allow risk stratification of the severity of the ophthalmologic manifestation. However, additional studies involving larger cohorts are needed to replicate our observations and conduct powered analyses to more formally risk-stratify based on genotype, highlighting the importance of multicenter collaborations in rare disease research.

Despite ample success in reducing coronary artery disease (CAD) risk through reduction of low-density lipoprotein cholesterol (LDL-C), there remains substantial residual risk.1–4 Recent prospective studies have demonstrated that elevated triglycerides (TGs) are independent predictors of CAD risk.5–9 Furthermore, TGs are strongly associated with incident CAD events in patients with low LDL-C levels treated with statin.10 Thus, triglyceride-rich lipoproteins (TRLs) offer a potentially orthogonal risk factor to LDL-C for lowering CAD risk, but only if TRLs are causally associated with atherosclerotic disease.11 Human genetics has the potential to reveal the causal relationships of biomarkers found to be associated with disease outcomes.12–15 For example, genetic variants associated with plasma LDL-C levels are consistently associated with CAD risk in the right direction,15–18 consistent with a causal relationship. Importantly, similar studies have causally implicated the key TG-regulating enzyme lipoprotein lipase (LPL) in CAD risk. A common gain-of-function LPL variant, S447X, confers an antiatherogenic lipid profile characterized by low levels of TGs, and in several studies, it has been associated with lower incidence of vascular disease or myocardial infarction (MI).19–25 Conversely, several loss-of-function (LOF) LPL variants associated with elevated TG levels have been reported to be associated with increased CAD risk.21,26 Furthermore, multiple genome-wide association studies in the last 5 years have identified common noncoding variants at the LPL gene locus associated with both TG and CAD risk in the same direction.27–29 Beyond LPL itself, common variants that influence TG levels are significantly associated with CAD risk even after adjusting for their effects on other lipid traits.30 Do et al30 surveyed 185 single-nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with ≥1 plasma lipid trait and identified a subset of …

This study provides a detailed genotype and phenotype analysis of a large longitudinal cohort of Kabuki Syndrome (KS) from a single center in China. From July 2017 to July 2024, participants were enrolled at Shanghai Children's Medical Center. Variants in KMT2D or KDM6A were identified through whole exome sequencing. Phenotype data included prenatal and perinatal history, neonatal, childhood and adolescence evaluations. A total of 104 KS individuals fullfiled 362 outpatient visits, with an average follow-up of 2.58 years and a median follow-up time of 1.75 years. Growth curves were plotted based on 433 height data points. Among the patients, 27.08% had congenital heart defects (CHD), and 3 patients were identified with anomalous pulmonary venous connection as a new KS phenotype. KS patients showed facial feature heterogeneity, patients with atypical facial features associated with a older diagnosis age and a more diverse and severe phenotype. Among the 99 KS patients who provided facial photographs, the Face2Gene software was able to make accurate diagnoses in 85 individuals. The remaining 14 individuals may have had incorrect diagnoses because the provided photographs were not frontal facial images.Conclusion: This study offered a comprehensive description of a Chinese KS cohort, and provided the first growth curves and a detailed CHD phenotype spectrum of Chinese KS patients. Our findings also suggest that, despite requirements for photograph quality, facial recognition software will be of significant value in the clinical diagnosis of KS.What is Known:• Kabuki syndrome is a rare disease that affects multiple systems. • Short stature is one of the common clinical manifestations of Kabuki syndrome.What is New:• The genotypes and phenotypes of patients with Kabuki syndrome in China have been described in detail. • Growth curves for patients with Kabuki syndrome in China have been established.

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5–10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

ObjectiveKabuki Syndrome (KS), caused by haploinsufficiency in lysine methyltransferase KMT2D, is a multi‐system disease characterized by distinct facial dysmorphisms, mild‐to‐moderate intellectual disability, renal and cardiac abnormalities, short stature and humoral immune deficiency. Many of the tissues in which these abnormalities manifest are derived from or developmentally modulated by the neural crest cell (NCC) lineage. This study’s objective was to determine which features of the KS phenotype can be directly linked to genetic and epigenetic dysregulation in KMT2D haploinsufficient NCCs.MethodsPeripheral blood mononuclear cells from a human donor haploinsufficient for KMT2D (KS patient, KMT2D+/−) or wild type (WT) control were used to generate induced pluripotent stem (iPS) cells. WT and KS NCCs were generated from WT and KS iPS cells, respectively. Whole transcriptome RNA sequencing (RNAseq) was performed on iPS cells (WT and KS) and NCCs (WT and KS) to characterize differential gene expression. Chromatin immunoprecipitation sequencing (ChIPseq) of histone 3 lysine 4 trimethylation (H3K4Me3) and histone 3 lysine 27 acetylation (H3K27Ac) was performed on NCCs (WT and KS) to characterize differential histone modifications at gene regulatory elements. Analysis of RNAseq and ChIPseq data was performed using BioWardrobe platform.ResultsGene set enrichment analysis of transcriptome data indicates that, compared to WT NCCs, KMT2D haploinsufficient NCCs have ectopic expression of several genes critical to normal NCC organization, morphogenesis and tissue differentiation, including NCC transcriptional repressor Msh homeobox 2 (MSX2). Analysis also identified several genes with decreased expression in KMT2D+/− NCCs, including transcription factor AP‐2 alpha (TFAP2A), which serves as a master regulator of NCC lineage progression. ChIPseq data indicate differential enrichment of H3K4Me3 and H3K27Ac histone modifications at the TFAP2A locus in WT compared to KS NCCs, which suggests that TFAP2A may have a direct role in the impaired differentiation of NCCs in KS. Further studies to explore the roles of TFAP2A and other genes identified by these data are underway.ConclusionThese results show that KMT2D haploinsufficiency impairs differentiation of the NCC lineage cells through epigenetic and transcriptomic dysregulation, thus supporting the classification of KS as a neurocristopathy.Support or Funding InformationNIH T32 Training Grant 5T32AI060515‐14 (WJL), R35 DE027557 (SB), Center for Pediatric Genomics Cincinnati Research Foundation (AWL).

Kabuki syndrome (KS) (OMIM#147920) is a multiple congenital anomaly/mental retardation syndrome. Recently, pathogenic variants in KMT2D and KDM6A were identified as the causes of KS in 55.8-80.0% of patients. To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A. Whole-exome sequencing and direct sequencing for validation were performed in 12 patients with a clinical suspicion of KS. KMT2D and KDM6A mutations were identified in 11 (91.7%) patients. No recurrent mutation was observed, and 10 out of the 11 mutations found were novel. KMT2D mutations were detected in 10 patients, including four small deletions or insertions and four nonsense and two missense mutations. One girl had a novel splice-site mutation in KDM6A. Each patient had a unique individual mutation. This is the first report of mutational analysis via exome sequencing in Korean patients with KS. Because the mutation-detection rate was high in this study, rigorous mutation analysis of KMT2D and KDM6A may be an important tool for the early diagnosis and genetic counseling of Korean patients with KS.

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.

Introduction: Kabuki syndrome (KS) is a rare genetic disorder with a prevalence of 1/86,000–1/32,000. Pathogenic variants in the KMT2D and KDM6A genes are responsible for the majority of KS cases and are inherited in an autosomal dominant and X-linked manner, respectively. Despite KS being genetically pleiotropic, specific phenotypic features, such as hypotonia, developmental disorders, mental retardation, dermatoglyphic and facial abnormalities, are widely manifested among patients with KS. Only few prenatal findings have been associated with KS so far. Case Presentation: This report highlights an interesting and infrequent case of a neonate with severe midface hypoplasia and multiple congenital anomalies, which were noted on the 2nd trimester antenatal scan. The degree of hypoplasia was indicative of chondrodysplasia punctata, but there was no relevant pregnancy history or other features of a skeletal dysplasia. The pregnancy was complicated by preterm premature rupture of membranes. The neonate was born at 27 weeks of gestation and died 16 days later, due to complications of prematurity. Whole exome sequencing identified a novel de novo KMT2D pathogenic variant. Conclusion: Although midface hypoplasia has been previously reported in individuals with KS, the severity noted in the index individual is an unusual feature of the syndrome. Introduction: Kabuki syndrome (KS) is a rare genetic disorder with a prevalence of 1/86,000–1/32,000. Pathogenic variants in the KMT2D and KDM6A genes are responsible for the majority of KS cases and are inherited in an autosomal dominant and X-linked manner, respectively. Despite KS being genetically pleiotropic, specific phenotypic features, such as hypotonia, developmental disorders, mental retardation, dermatoglyphic and facial abnormalities, are widely manifested among patients with KS. Only few prenatal findings have been associated with KS so far. Case Presentation: This report highlights an interesting and infrequent case of a neonate with severe midface hypoplasia and multiple congenital anomalies, which were noted on the 2nd trimester antenatal scan. The degree of hypoplasia was indicative of chondrodysplasia punctata, but there was no relevant pregnancy history or other features of a skeletal dysplasia. The pregnancy was complicated by preterm premature rupture of membranes. The neonate was born at 27 weeks of gestation and died 16 days later, due to complications of prematurity. Whole exome sequencing identified a novel de novo KMT2D pathogenic variant. Conclusion: Although midface hypoplasia has been previously reported in individuals with KS, the severity noted in the index individual is an unusual feature of the syndrome.

Background Kabuki Syndrome (KS) is a rare multiple congenital anomaly syndrome originally described in 1981 by Japanese clinicians. KS belongs to the family of chromatinopathies, a group of disorders characterized by abnormalities in chromatin regulation due to germline mutations in the KMT2D or KDM6A genes. KS is characterized by five cardinal manifestations: (1) postnatal growth deficiency, (2) skeletal anomalies, (3) dermatoglyphic anomalies – including persistent fetal pads, (4) mild-to-moderate intellectual disability, and (5) typical facial features. Purpose Ocular abnormalities have been reported in more than one-third of patients with KS, but abnormalities involving the retina are rare. Currently, five accounts describing patients with KS and documented macular lesions exist within the literature. However, only two of these reports provide concurrent genetic confirmation. Findings We describe the unique case of a female infant with molecularly confirmed KS due to a novel pathogenic variant in KMT2D who presented with retinopathy of prematurity (ROP) and bilateral macular lesions. Conclusions Although our patient accounts for the sixth known case of foveal lesions associated with KS, she represents the third molecularly confirmed case of a de novo, nonsense KMT2D variant with macular abnormalities. In silico analysis with the prediction program MutationTaster found the mutation to be deleterious. Genetic testing, along with ophthalmologic examination and multimodal imaging, are indispensable tools for physicians, especially when confronted with patients suspected of having KS. When effectively used together, these tools can facilitate vision-preserving strategies.

The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9–99.9%, p < 0.001) and distinguish KS1 from KS2 with an empirical Area Under the Curve (AUC) of 0.805 (0.729–0.880, p < 0.001). We report an automatic detection model for KS with high performances (AUC 0.993 and accuracy 95.8%). We were able to distinguish patients with KS1 from KS2, with an AUC of 0.805. These results outperform the current commercial AI-based solutions and expert clinicians.

Background: Muscular dystrophies are a heterogeneous group of inherited disorders that cannot be diagnosed clinically due to overlapping clinical phenotypes. Whole-exome sequencing is considered as the diagnostic strategy of choice in these cases. In this study we aimed to determine the mutational spectrum of multiplex ligation-dependent probe amplification (MLPA)-negative muscular dystrophy patients in Pakistan using whole-exome sequencing. Subsequently the mutations identified via WES were used to screen additional dystrophinopathy patients by Sanger sequencing. Materials and Methods: DNA extracted from the peripheral blood of three MLPA-negative muscular dystrophy patients was sent for whole-exome sequencing. The identified variants in these 3 patients were then checked in 18 dystrophinopathy patients using Sanger sequencing. Results: Four missense variants and one nonsense variant in the Duchenne muscular dystrophy (DMD) gene were detected. WES diagnosed a DMD patient carrying a nonsense variant c.4375C>T (rs398123953) who can benefit from Ataluren therapy. The other two patients carried missense variant (c.572G>T) in the YARS2 gene (rs11539445) labeling them as patients of MLASA (myopathy, lactic acidosis, and sideroblastic anemia). The identified missense and nonsense variants in the DMD gene were detected in 18 clinically diagnosed dystrophinopathy patients using Sanger sequencing. Three missense variants were detected in our cohort of 18 dystrophinopathy patients. One missense variant c.3406A>T (rs3827462) and a nonsense variant c.4375C>T (rs398123953) were not detected in our cohort of 18 dystrophinopathy patients. Conclusions: Whole-exome sequencing identified a nonsense variant in Pakistani muscular dystrophy patients, which is amenable to treatment by Ataluren and a missense variant in YARS2 gene responsible for causing MLASA.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa–Kuroki) syndrome (MIM#147920). To further elucidate the genotype–phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2‐Kabuki score 0–10). Sequencing of the full coding region and intron–exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice‐site mutations, 34 of which were novel. In five additional patients, novel, i.e. non‐dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median ‘MLL2‐Kabuki score’ of 6) as compared to the patients without MLL2 mutations (median ‘MLL2‐Kabuki score’ of 5), a significant difference (p &lt; 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.