Summary
Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents of children with severe epileptic ...encephalopathies. Here we aim to investigate the frequency of mosaicism in the parents of children with epilepsy caused by alleged de novo variants. We tested parental genomic DNA derived from different tissues for 75 cases using targeted next‐generation sequencing. Five parents (6.6%) showed mosaicism at minor allele frequencies of 0.8%‐29% for the pathogenic variant detected in their offspring. Parental mosaicism was observed in the following genes: SCN1A, SCN2A, SCN8A, and STXBP1. One of the identified parents had epilepsy himself. Our results show that de novo events can occur already in parental tissue and in some cases can be detected in peripheral blood. Consequently, parents affected by low‐grade mosaicism are faced with an increased recurrence risk for transmitting the pathogenic variant, compared to the overall recurrence risk for a second affected child estimated at approximately 1%. However, testing for parental somatic mosaicism will help identifying those parents who truly are at higher risk and will significantly improve genetic counseling in the respective families.
We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic ...setting.
We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.
Genes with highest frequencies of ultrarare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1, concordant with the two other epilepsy cohorts we investigated. In only 46% of the analyzed 262 dominant and X-linked panel genes ultrarare variants in patients were reported. Among genes with contradictory evidence of association with epilepsy, CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 showed equal frequencies in cases and controls.
We show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultrarare variants in individuals with NDD+E to the community.
We assessed in vivo lamina cribrosa (LC) position within the optic nerve head in glaucoma.
For interindividual comparison, glaucoma patients at various stages and normal subjects were recruited. For ...intraindividual, intereye comparison, glaucoma patients with visual field (VF) defects in only one eye were recruited separately. Serial horizontal and vertical enhanced depth imaging optical coherence tomography (EDI OCT) B-scans of the optic nerve head were obtained prospectively from each participant. Mean and maximum anterior LC depths were measured in 11 equally spaced horizontal B-scans, excluding the LC insertion area under the Bruch's membrane and scleral rim.
Totals of 47 glaucomatous eyes (47 patients; VF mean deviation, -12.7±8.2 dB) and 57 normal eyes (57 subjects) were enrolled for the interindividual comparison. Mean and maximum LC depths were significantly greater in the glaucomatous than in the normal eyes in all 11 scans (all P<0.03). There were 54 glaucoma patients with VF defects in only one eye (VF mean deviation, -15.6±8.8 dB) included in the intereye comparison. Mean and maximum LC depths were significantly greater in the eyes with VF defects than in the fellow eyes with no VF defects in all 11 scans (all P<0.01).
The central and midperipheral LC is located more posteriorly in glaucomatous than in normal eyes, as well as in eyes with VF defects compared to fellow eyes with no VF defects. These results support the concept of posterior LC displacement in glaucoma and provide the basis for future in vivo human studies.
Objectives: The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ ...between bipolar disorder (BD) and controls.
Methods: The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5′ region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls.
Results: Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073).
Conclusions: Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.
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