Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment

Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers 4 of the gene's 5 exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing Mini-Mental State Examination (MMSE) scores and diagnoses of dementia, we did not find any significant differences between TYROBP deletion carriers and noncarriers (all p-values >0.5). Neuropathological analysis of 2 deletion carriers (aged 89 and 94 years) demonstrated only minimal beta amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Diagnostic implications of genetic copy number variation in epilepsy plus

OBJECTIVE: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. // METHODS: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. // RESULTS: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. // SIGNIFICANCE: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes

A randomized controlled trial with female teachers:are there differences between and within the outcomes in voice therapy groups with and without carryover strategies?

Abstract Purpose: We investigated if outcomes differ between voice therapy groups systematically using carryover strategies (attempts to generalize new vocal skills outside the clinic) and voice therapy with no emphasis on any generalizing process (here referred to as traditional voice therapy). Method: A randomized controlled trial was conducted. Participants (53 female teachers with voice disorders) were randomly allocated into three groups: Carryover (a group receiving voice therapy using carryover strategies), Trad (a group receiving voice therapy with no emphasis on any generalizing process), Controls (a group on an eight-week non-therapy period). Prior to the trial a direct laryngoscopy was performed with a videolaryngostroboscopy system and/or nasofaryngofiberoscope with stroboscopy. Before and after therapy and at follow-up a voice evaluation protocol was implemented consisting of subjective assessments (Questionnaire on Voice Symptoms, and the Voice Activity and Participation Profile; VAPP), and objective measurements (voice sample recordings, acoustic analysis [SPL, sound pressure level; f₀, fundamental frequency; alpha-ratio, tilt of the sound spectrum slope]). Results: No differences were found between the groups. Several significant changes occurred within the groups between initial phase vs. post-therapy and initial phase vs. follow-up. In the Carryover group text reading the alpha-ratio became lower (P = 0.011) and spontaneous speech f₀ increased (P = 0.024) after the therapy and [a:] SPL increased (P = 0.042) at follow-up. In the Trad group post-therapy [a:] alpha-ratio became lower (P = 0.012) and spontaneous speech f₀ decreased (P = 0.034). After therapy VAPP scores showed improvement in voice-related quality of life in both therapy groups (Carryover P = 0.003; Trad P = 0.01) but only in Carryover at follow-up (P = 0.000). Voice symptoms decreased in the Carryover group post-therapy (P = 0.001) and at follow-up (P = 0.000) and after Controls’ eight-week non-therapy period (P = 0.003). Conclusions: The results showed that carryover strategies give no additional advantages in voice therapy. However, the decreasing trend in the Carryover group’s voice complaints at follow-up would suggest that carryover strategies may have long-lasting effects. The results also confirm that voice therapy is efficient in improving voice-related quality of life

Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk