The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.

Background The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. Methods A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. Results Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28–174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. Conclusions A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1 . An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker. Electronic supplementary material The online version of this article (10.1186/s11689-019-9276-y) contains supplementary material, which is available to authorized users.

Summary Objective The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability1. Individuals with loss of function mutations in SHANK3 have intellectual disability, autism and variably, epilepsy2–5. The spectrum of seizure semiologies and electroencephalographic (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately two percent of individuals with moderate to severe intellectual disabilities and one percent of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations. Methods A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss of function mutation in SHANK3 identified through whole exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset and efficacy of therapy were determined. Electroencephalograms were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist. Results There is a wide spectrum of seizure semiologies, frequencies and severity in individuals with SHANK3 mutations. There are no specific electroencephalographic abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure. Significance All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings or electroencephalogram findings were present in the majority of individuals with SHANK3 mutations.