Thousand and one amino‐acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen‐activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant‐negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.
ilated cardiomyopathy (DCM) is a nonischemic, nontoxic, noninfectious, or nonvalvular heart muscle disease characterized by left ventricular or biventricular systolic dysfunction. 1,2 Typical onset of the disease is in the fourth or fifth decade of life and it affects predominantly male individuals with a male-to-female ratio of 3:1. 2 Although a specific cause might be unknown in a non-negligible number of patients, to date, more than one-third of familial forms and approximately 25% of sporadic cases have positive genetic testing for pathogenic (P) or likely pathogenic (LP) variants. [3][4][5][6] Recent evidence highlights the importance of specific genotypes in determining the prognosis of patients with DCM, either alone or in combination with environmental factors. [7][8][9][10][11] Contemporary analyses highlight that DCM is increasingly diagnosed in older patients 12 and a late-onset (ie, age >60 years) form of DCM could differ from more typical-onset DCM presentations. 13 However, the genetic background and the prognostic impact of genetic characterization among patients with DCM presenting who are older than 60 years are largely unknown.The aim of the present study was to investigate the genetic background and the natural history of a large international cohort of individuals with DCM presenting in individuals older than 60 years to assess the importance of genetic testing in those patients.
Methods
Study PopulationFor the present study, we included all consecutive patients with DCM older than 60 years at the time of diagnosis (ie, lateonset DCM), with available genetic testing analysis, from 7 international tertiary centers worldwide: Cardiovascular IMPORTANCE Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM).OBJECTIVE To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM.
DESIGN, SETTING, AND PARTICIPANTSA population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants.
MAIN OUTCOMES AND MEASURESThe study outcome was all-cause mortality.RESULTS A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers o...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.