Genetic burden of TNNI3K in diagnostic testing of patients with dilated cardiomyopathy and supraventricular arrhythmias

BACKGROUND:Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS:We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays. RESULTS:We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS:Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.Genetics of disease, diagnosis and treatmen

The evolution of language: a comparative review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful "just so stories" about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the ‘‘descended larynx’ ’ of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation

Apathy Associated With Impaired Recognition of Happy Facial Expressions in Huntington's Disease.

OBJECTIVES: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson's disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington's disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. METHODS: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment - short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S. RESULTS: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington's Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score. CONCLUSIONS: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453-461)

Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility (Nature Genetics, (2022), 54, 3, (232-239), 10.1038/s41588-021-01007-6)

In the version of this Article initially published, Federico Manevy’s name appeared with a middle initial in error. The name has been corrected in the HTML and PDF versions of the Article. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022.Hjerteforeningen; Fondation Leduc

Radar Observations and Physical Modeling of Asteroid 6489 Golevka

44> Author AC voice fax JPL E-mail mailstop ----------------------------------------------------------------------------- Hudson 509 335-0922 335-3818 [email protected] Ostro 818 354-3173 354-9476 300-233 [email protected] Jurgens 818 354-4974 354-6825 238-420 [email protected] Rosema 818 393-2629 354-9476 300-233 [email protected] Giorgini 818 393-3107 393-1159 301-150 [email protected] Winkler 760 255-8259 255-8515 DSCC-61 [email protected] Rose 760 255-8259 255-8515 DSCC-61 [email protected] Choate 760 255-8259 255-8515 DSCC-74 [email protected] Cormier 760 255-8358 255-8554 DSCC-74 [email protected] Franck 818 354-6842 354-6825 238-420 [email protected] Frye 818 354-6874 354-6825 238-420 [email protected] Howard 818 354-8753 354-8153 125-177 [email protected] Kelley 760 255-8358 255-8554 DSCC-74 [email protected] Littlefa

Association of CAG Repeats With Long-term Progression in Huntington Disease

Neuro Imaging Researc