Background: Approximately 7% of clinically referred youth exhibit profound impairment in the ability to regulate their affect, behavior, and cognition. This phenotype – often referred to as dysregulation – has been associated with a multitude of negative outcomes. Symptom overlap between dysregulation and other psychological disorders has generated debate regarding whether DP constitutes a distinct syndrome characterized by intense, persistent irritability or is merely the combination of symptoms from disruptive or mood disorders. In order to elucidate this question, the current study examined the transdiagnostic continuities and discontinuities in three RDoC constructs (frustrative non-reward, acute threat, and cognitive control) proposed to be mechanisms of irritability Method: Participants were 294 children ages 7-17 (M=10.94; 67% male). Emotional and behavioral symptoms were measured using the Child Behavior Checklist and the Kiddie Schedule for Affective Disorders and Schizophrenia. Frustrative non-reward was measured using a frustration-induction Go/No-Go paradigm during which heart rate variability was indexed by respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). Acute threat was measured using an Emotional Faces computer paradigm in conjunction with an eyetracker/pupilometer. Cognitive control was assessed with the Behavioral Rating Inventory of Executive Function (BRIEF), Delis-Kaplan Executive Function System (D-KEFS) and Stop Signal Task (SST). Results: Symptoms of dysregulation and non-episodic irritability were strongly, positively related. Due to a lack of demonstrated construct validity for the hypothesized RDoC constructs of frustrative non-reward, acute threat, and cognitive control, two alternative mechanisms—SNS response and cognitive dyscontrol of emotion—were derived from the data. Results showed that blunted sympathetic responsivity and poor executive control in response to emotion were predictive of more severe irritability symptoms. Finally, moderation analyses showed that among highly dysregulated children, low levels of sympathetic responsiveness were associated with more severe irritability symptoms. Conclusions: Despite phenotypic overlap with other forms of developmental psychopathology, dysregulated children can be distinguished based on the severity of their irritability symptoms. This supports the conceptualization of dysregulation as a unique syndrome characterized by intense and persistent irritability and lends credence to the novel diagnosis of DMDD. Furthermore, cognitive, behavioral and physiological patterns identified in this study suggest that difficulties with processing negative emotion—as opposed to frustration or threat specifically—may constitute a vulnerability for irritability.