RESUMO
SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.
Assuntos
Ansiedade/genética , Transtorno do Espectro Autista/genética , Metilação de DNA , Epilepsia/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , Adolescente , Adulto , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Proteínas F-Box/genética , Feminino , Marcadores Genéticos , Humanos , Recém-Nascido , Histona Desmetilases com o Domínio Jumonji/genética , MasculinoRESUMO
Beckwith-Wiedemann syndrome (BWS) is caused due to the disturbance of imprinted genes at chromosome 11p15. The molecular confirmation of this syndrome is possible in approximately 85% of the cases, whereas in the remaining 15% of the cases, the underlying defect remains unclear. The goal of our research was to identify new epigenetic loci related to BWS. We studied a group of 25 patients clinically diagnosed with BWS but without molecular conformation after DNA diagnostics and performed a whole genome methylation analysis using the HumanMethylation450 Array (Illumina).We found hypermethylation throughout the methylome in two BWS patients. The hypermethylated sites in these patients overlapped and included both non-imprinted and imprinted regions. This finding was not previously described in any BWS-diagnosed patient.Furthermore, one BWS patient exhibited aberrant methylation in four maternally methylated regions-IGF1R, NHP2L1, L3MBTL, and ZDBF2-that overlapped with the differentially methylated regions found in BWS patients with multi-locus imprinting disturbance (MLID). This finding suggests that the BWS phenotype can result from MLID without detectable methylation defects in the primarily disease-associated loci (11p15). Another patient manifested small but significant aberrant methylation in disease-associated loci at 11p near H19, possibly confirming the diagnosis in this patient.
Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Metilação de DNA , Sequenciamento Completo do Genoma/métodos , Síndrome de Beckwith-Wiedemann/genética , Cromossomos Humanos Par 11/genética , Feminino , Impressão Genômica , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , FenótipoRESUMO
Oxytocin receptor gene (OXTR) DNA-methylation levels have been associated with trauma-exposure, mood- and anxiety disorders, and social processes relevant to posttraumatic stress disorder (PTSD). We hypothesized that OXTR methylation may play a role in the neurobiological underpinnings of PTSD. In the current study, we compared OXTR methylation between PTSD patients (nâ¯=â¯31, 14 females) and trauma-exposed controls (nâ¯=â¯36, 19 females). Additionally, the association between OXTR methylation and PTSD symptom severity and amygdala reactivity to an emotional faces task was assessed, as a neural hallmark of PTSD. DNA-methylation was investigated in the CpG island located at exon 3 of the OXTR, previously associated with OXTR expression. We observed a significant interaction between PTSD-status, sex and CpG-position on methylation levels. Post-hoc testing revealed that methylation levels at two specific CpG-sites were significantly higher in PTSD females compared to female trauma-exposed controls and PTSD males (CpGs Chr3:8809437, Chr3:8809413). No significant differences in methylation were observed between male PTSD patients and controls. Furthermore, within PTSD females, methylation in these CpG-sites was positively associated with anhedonia symptoms and with left amygdala responses to negative emotional faces, although this was no longer significant after stringent correction for multiple-comparisons. Though the modest size of the current sample is an important limitation, we are the first to report on OXTR methylation in PTSD, replicating previously observed (sex-specific) associations of OXTR methylation with other psychiatric disorders.
