Dataset Information

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

ABSTRACT: Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

SUBMITTER: Sobreira N

PROVIDER: S-EPMC5865196 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

Sobreira Nara N Brucato Martha M Zhang Li L Ladd-Acosta Christine C Ongaco Chrissie C Romm Jane J Doheny Kimberly F KF Mingroni-Netto Regina C RC Bertola Debora D Kim Chong A CA Perez Ana Ba AB Melaragno Maria I MI Valle David D Meloni Vera A VA Bjornsson Hans T HT

European journal of human genetics : EJHG 20171107 12

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusi ...[more]

PMID: 29255178

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Project description:Kabuki syndrome (KS) is a Mendelian Disorder of the Epigenetic Machinery (MDEM) caused by loss of function variants in either of two genes involved in the regulation of histone methylation, KMT2D (34-76%) or KDM6A (9-13%). Previously, representative neurobehavioral deficits of KS were recapitulated in a mouse model, emphasizing the role of KMT2D in brain development, specifically in ongoing hippocampal neurogenesis in the granule cell layer of the dentate gyrus. Interestingly, anxiety, a phenotype that has a known association with decreased hippocampal neurogenesis, has been anecdotally reported in individuals with KS. In this study, anxiety and behavior were assessed in a cohort of 60 individuals with molecularly confirmed KS and 25 unaffected biological siblings, via questionnaires (SCARED/GAS-ID and CBCL/ABCL). Participant age ranged from 4 to 43 years old, with 88.3% of participants having a pathogenic variant in KMT2D, and the rest having variants in KDM6A. In addition, data was collected on adaptive function and positive affect/quality of life in participants with KS using appropriate online surveys including ABAS-III and PROMIS Positive Affect. Survey scores were compared within the KS participants across age groups and between KS participants and their unaffected siblings. We found that children with KS have significantly higher anxiety scores and total behavior problem scores than their unaffected siblings (p = 0.0225, p < 0.0001). Moreover, a large proportion of affected individuals (22.2% of children and 60.0% of adults) surpassed the established threshold for anxiety; this may even be an underestimate given many patients are already treated for anxiety. In this sample, anxiety levels did not correlate with level of cognitive or adaptive function in any KS participants, but negatively correlated with positive affect in children with KS (p = 0.0005). These findings indicate that anxiety is a common neurobehavioral feature of KS. Providers should therefore carefully screen individuals with KS for anxiety as well as other behavioral issues in order to allow for prompt intervention. Neurobehavioral anxiety measures may also prove to be important outcome measures for clinical trials in KS.

Project description:Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. The aim of this study was to identify the epigenotype-phenotype correlations of these patients using quantitative DNA methylation analysis. One hundred and four subjects with clinically suspected BWS were enrolled in this study. All of the subjects had been referred for diagnostic testing which was conducted using methylation profiling of H19-associated imprinting center (IC) 1 and KCNQ1OT1-associated IC2 in high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between the quantitative DNA methylation status and clinical manifestations of the enrolled subjects were analyzed. Among the 104 subjects, 19 had IC2 hypomethylation, 2 had IC1 hypermethylation, and 10 had paternal uniparental disomy (pUPD). The subjects with IC2 hypomethylation were characterized by significantly more macroglossia but less hemihypertrophy compared to the subjects with pUPD (p < 0.05). For 19 subjects with IC2 hypomethylation, the IC2 methylation level was significantly different (p < 0.05) between the subjects with and without features including macroglossia (IC2 methylation level: 11.1% vs. 30.0%) and prenatal or postnatal overgrowth (8.5% vs. 16.9%). The IC2 methylation level was negatively correlated with birth weight z score (p < 0.01, n = 19) and birth height z score (p < 0.05, n = 13). For 36 subjects with clinically diagnosed BWS, the IC2 methylation level was negatively correlated with the BWS score (r = -0.592, p < 0.01). The IC1 methylation level showed the tendency of positive correlation with the BWS score without statistical significance (r = 0.137, p > 0.05). Lower IC2 methylation and higher IC1 methylation levels were associated with greater disease severity in the subjects with clinically diagnosed BWS. Quantitative DNA methylation analysis using the MassARRAY assay could improve the detection of epigenotype-phenotype correlations, which could further promote better genetic counseling and medical care for these patients.

Dataset Information

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

Publications

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

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