UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In C. elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.

UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.

MAPK8IP3 (unc-16/JIP3) is a neurodevelopmental-disorder associated gene that can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.

Visual experience induces 4-8 Hz synchrony between V1 and higher-order visual areas.

Visual perceptual experience induces persistent 4-8 Hz oscillations in the mouse primary visual cortex (V1), encoding visual familiarity. Recent studies suggest that higher-order visual areas (HVAs) are functionally specialized and segregated into information streams processing distinct visual features. However, whether visual memories are processed and stored within the distinct streams is not understood. We report here that V1 and lateromedial (LM), but not V1 and anterolateral, become more phase synchronized in 4-8 Hz after the entrainment of visual stimulus that maximally induces responses in LM. Directed information analysis reveals changes in the top-down functional connectivity between V1 and HVAs. Optogenetic inactivation of LM reduces post-stimulus oscillation peaks in V1 and impairs visual discrimination behavior. Our results demonstrate that 4-8 Hz familiarity-evoked oscillations are specific for the distinct visual features and are present in the corresponding HVAs, where they may be used for the inter-areal communication with V1 during memory-related behaviors.

Autism candidate gene rbm-26 ( RBM26/27 ) regulates MALSU-1 to protect against mitochondrial dysfunction during axon development.

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and ADHD. However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26 , the C. elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against neurodevelopmental defects by negatively regulating expression of the MALSU-1 mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with neurodevelopmental defects, including errors in axon targeting and axon degeneration. Using an unbiased screen, we identified the mRNA for the MALSU-1 mitoribosomal assembly factor as a binding partner for RBM-26. RBM-26 negatively regulates the expression of malsu-1 mRNA and MALSU-1 protein, and genetic analysis indicates that this interaction is required to protect against neurodevelopmental defects. Moreover, biochemical evidence suggests that excess levels of MALSU-1 disrupt the biogenesis of mitoribosomes in rbm-26 mutants. These observations reveal a mechanism that can protect mitochochondrial function to prevent neurodevelopmental defects and suggest that disruptions in this process can cause neurodevelopmental disorders.

UNC-116 and UNC-16 function with the NEKL-3 kinase to promote axon targeting.

KIF5C is a kinesin-1 heavy chain that has been associated with neurodevelopmental disorders. Although the roles of kinesin-1 in axon transport are well known, little is known about how it regulates axon targeting. We report that UNC-116/KIF5C functions with the NEKL-3/NEK6/7 kinase to promote axon targeting in Caenorhabditis elegans. Loss of UNC-116 causes the axon to overshoot its target and UNC-116 gain-of-function causes premature axon termination. We find that loss of the UNC-16/JIP3 kinesin-1 cargo adaptor disrupts axon termination, but loss of kinesin-1 light chain function does not affect axon termination. Genetic analysis indicates that UNC-16 functions with the NEKL-3 kinase to promote axon termination. Consistent with this observation, imaging experiments indicate that loss of UNC-16 and UNC-116 disrupt localization of NEKL-3 in the axon. Moreover, genetic interactions suggest that NEKL-3 promotes axon termination by functioning with RPM-1, a ubiquitin ligase that regulates microtubule stability in the growth cone. These observations support a model where UNC-116 functions with UNC-16 to promote localization of NEKL-3 in the axon. NEKL-3, in turn, functions with the RPM-1 ubiquitin ligase to promote axon termination.

Importance of social vulnerability on long-term outcomes after heart transplantation.

The relationship between social determinants of health and outcomes after heart transplantation has not been examined. The social vulnerability index (SVI) uses United States census data to determine the social vulnerability of every census tract based on 15 factors. This retrospective study seeks to examine the impact of SVI on outcomes after heart transplantation. Adult heart recipients who received a graft between 2012 and 2021 were stratified into SVI percentiles of <75% and SVI of ≥75%. The primary endpoint was survival. The median SVI was 48% (interquartile range: 30%-67%) among 23 700 recipients. One-year survival was similar between groups (91.4 vs 90.7%, log-rank P = .169); however, 5-year survival was lower among individuals living in vulnerable communities (74.8% vs 80.0%, P < .001). This finding persisted despite risk adjustment for other factors associated with mortality (survival time ratio 0.819, 95% confidence interval: 0.755-0.890, P < .001). The incidences of 5-year hospital readmission (81.4% vs 75.4%, P < .001) and graft rejection (40.3% vs 35.7%, P = .004) were higher among individuals living in vulnerable communities. Individuals living in vulnerable communities may be at increased risk of mortality after heart transplantation. These findings suggest there is an opportunity to focus on these recipients undergoing heart transplantation to improve survival.

De-implementation of Axillary Dissection in Women Undergoing Mastectomy for Breast Cancer.

BACKGROUND: Completion axillary lymph node dissection (cALND) was standard treatment for breast cancer with positive sentinel lymph nodes (SLNs) until 2011, when data from the Z11 and AMAROS trials challenged its survival benefit in early stage breast cancer. We assessed the contribution of patient, tumor, and facility factors on cALND use in patients undergoing mastectomy and SLN biopsy. PATIENTS AND METHODS: Using the National Cancer Database, patients diagnosed from 2012 to 2017 who underwent upfront mastectomy and SLN biopsy with at least one positive SLN were included. A multivariable mixed effects logistic regression model was used to determine the effect of patient, tumor, and facility variables on cALND use. Reference effect measures (REM) were used to compare the contribution of general contextual effects (GCE) to variation in cALND use. RESULTS: From 2012 to 2017, the overall use of cALND decreased from 81.3% to 68.0%. Overall, younger patients, larger tumors, higher grade tumors, and tumors with lymphovascular invasion were more likely to undergo cALND. Facility variables, including higher surgical volume and facility location in the Midwest, were associated with increased use of cALND. However, REM results showed that the contribution of GCE to the variation in cALND use exceeded that of the measured patient, tumor, facility, and time variables. CONCLUSIONS: There was a decrease in cALND use during the study period. However, cALND was frequently performed in women after mastectomy found to have a positive SLN. There is high variability in cALND use, mainly driven by interfacility practice variation rather than specific high-risk patient and/or tumor characteristics.

Sounding the Alarm: What Clinicians Need to Know about Physical, Emotional, and Cognitive Recovery After Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVE: We summarize the existing data on the occurrence of physical, emotional, and cognitive dysfunction associated with postintensive care syndrome (PICS) in adult survivors of venoarterial extracorporeal membrane oxygenation (VA-ECMO). DATA SOURCES: MEDLINE, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched. STUDY SELECTION: Peer-reviewed studies of adults receiving VA-ECMO for any reason with at least one measure of health-related quality of life outcomes or PICS at long-term follow-up of at least 6 months were included. DATA EXTRACTION: The participant demographics and baseline characteristics, in-hospital outcomes, long-term health outcomes, quality of life outcome measures, and prevalence of PICS were extracted. DATA SYNTHESIS: Twenty-seven studies met inclusion criteria encompassing 3,271 patients who were treated with VA-ECMO. The studies were limited to single- or two-center studies. Outcomes variables and follow-up time points evaluated were widely heterogeneous which limits comprehensive analysis of PICS after VA-ECMO. In general, the longer-term PICS-related outcomes of survivors of VA-ECMO were worse than the general population, and approaching that of patients with chronic disease. Available studies identified high rates of abnormal 6-minute walk distance, depression, anxiety, and posttraumatic stress disorder that persisted for years. Half or fewer survivors return to work years after discharge. Only 2 of 27 studies examined cognitive outcomes and no studies evaluated cognitive dysfunction within the first year of recovery. No studies evaluated the impact of targeted interventions on these outcomes. CONCLUSIONS: Survivors of VA-ECMO represent a population of critically ill patients at high risk for deficits in physical, emotional, and cognitive function related to PICS. This systematic review highlights the alarming reality that PICS and in particular, neurocognitive outcomes, in survivors of VA-ECMO are understudied, underrecognized, and thus likely undertreated. These results underscore the imperative that we look beyond survival to focus on understanding the burden of survivorship with the goal of optimizing recovery and outcomes after these life-saving interventions. Future prospective, multicenter, longitudinal studies in recovery after VA-ECMO are justified.

Development of the Illinois Surgical Quality Improvement Collaborative (ISQIC): Implementing 21 Components to Catalyze Statewide Improvement in Surgical Care.

INTRODUCTION: In 2014, 56 Illinois hospitals came together to form a unique learning collaborative, the Illinois Surgical Quality Improvement Collaborative (ISQIC). Our objectives are to provide an overview of the first three years of ISQIC focused on (1) how the collaborative was formed and funded, (2) the 21 strategies implemented to support quality improvement (QI), (3) collaborative sustainment, and (4) how the collaborative acts as a platform for innovative QI research. METHODS: ISQIC includes 21 components to facilitate QI that target the hospital, the surgical QI team, and the peri-operative microsystem. The components were developed from available evidence, a detailed needs assessment of the hospitals, reviewing experiences from prior surgical and non-surgical QI Collaboratives, and interviews with QI experts. The components comprise 5 domains: guided implementation (e.g., mentors, coaches, statewide QI projects), education (e.g., process improvement (PI) curriculum), hospital- and surgeon-level comparative performance reports (e.g., process, outcomes, costs), networking (e.g., forums to share QI experiences and best practices), and funding (e.g., for the overall program, pilot grants, and bonus payments for improvement). RESULTS: Through implementation of the 21 novel ISQIC components, hospitals were equipped to use their data to successfully implement QI initiatives and improve care. Formal (QI/PI) training, mentoring, and coaching were undertaken by the hospitals as they worked to implement solutions. Hospitals received funding for the program and were able to work together on statewide quality initiatives. Lessons learned at one hospital were shared with all participating hospitals through conferences, webinars, and toolkits to facilitate learning from each other with a common goal of making care better and safer for the surgical patient in Illinois. Over the first three years, surgical outcomes improved in Illinois. DISCUSSION: The first three years of ISQIC improved care for surgical patients across Illinois and allowed hospitals to see the value of participating in a surgical QI learning collaborative without having to make the initial financial investment themselves. Given the strong support and buy-in from the hospitals, ISQIC has continued beyond the initial three years and continues to support QI across Illinois hospitals.

Unmeasured factors are associated with the use of completion lymph node dissection (CLND) in melanoma.

BACKGROUND: Completion lymph node dissection (CLND) was the standard treatment for patients with melanoma with positive sentinel lymph nodes (SLN) until 2017 when data from the DeCOG-SLT and MLST-2 randomized trials challenged the survival benefit of this procedure. We assessed the contribution of patient, tumor and facility factors on the use of CLND in patients with surgically resected Stage III melanoma. METHODS: Using the National Cancer Database, patients who underwent surgical excision and were found to have a positive SLN from 2012 to 2017 were included. A multivariable mixed-effects logistic regression model with a random intercept for the facility was used to determine the effect of patient, tumor, and facility variables on the risk of CLND. Reference effect measures (REMs) were used to compare the contribution of contextual effects (unknown facility variables) versus measured variables on the variation in CLND use. RESULTS: From 2012 to 2017, the overall use of CLND decreased from 59.9% to 26.5% (p < 0.0001). Overall, older patients and patients with government-based insurance were less likely to undergo CLND. Tumor factors associated with a decreased rate of CLND included primary tumor location on the lower limb, decreasing depth, and mitotic rate <1. However, the contribution of contextual effects to the variation in CLND use exceeded that of the measured facility, tumor, time, and patient variables. CONCLUSIONS: There was a decrease in CLND use during the study period. However, there is still high variability in CLND use, mainly driven by unmeasured contextual effects.

The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1.

A family of giant KASH proteins, including C. elegans ANC-1 and mammalian Nesprin-1 and -2, are involved in organelle anchoring and are associated with multiple neurodevelopmental disorders including autism, bipolar disorder, and schizophrenia. However, little is known about how these proteins function in neurons. Moreover, the role of organelle anchoring in axon development is poorly understood. Here, we report that ANC-1 functions with the SLT-1 extracellular guidance cue to polarize ALM axon growth. This role for ANC-1 is specific to its longer ANC-1A and ANC-1C isoforms, suggesting that it is mechanistically distinct from previously described roles for ANC-1. We find that ANC-1 is required for the localization of a cluster of mitochondria to the base of the proximal axon. Furthermore, genetic and pharmacological studies indicate that ANC-1 functions with mitochondria to promote polarization of ALM axon growth. These observations reveal a mechanism whereby ANC-1 functions through mitochondria to polarize axon growth in response to SLT-1.

Patient characteristics and diagnostic tests associated with syncopal falls: A Southwestern surgical congress multicenter study.

BACKGROUND: Patients suspected of syncope frequently undergo laboratory and imaging studies to determine the etiology of the syncope. Variability exists in these workups across institutions. The purpose of this study was to evaluate the utilization and diagnostic yield of these workups and the patient characteristics associated with syncopal falls. METHODS: A multi-institutional retrospective review was performed on adult patients admitted after a fall between 1/2017-12/2018. Syncopal falls were compared to non-syncopal falls. RESULTS: 4478 patients were included. There were 795 (18%) patients with a syncopal fall. Electrocardiogram, troponin, echocardiogram, CT angiography (CTA), and carotid ultrasound were more frequently tested in syncope patients compared to non-syncope patients. Syncope patients had higher rates of positive telemetry/Holter monitoring, CTAs, and electroencephalograms. CONCLUSION: Patients who sustain syncopal falls frequently undergo diagnostic testing without a higher yield to determine the etiology of syncope.

A null allele in the wdfy-3 selective autophagy gene of C. elegans .

The C. elegans WDFY-3 protein is important for cargo selection during selective autophagy and for regulating axon termination. The C-terminal region of WDFY-3 contains BEACH, WD repeats, and FYVE-like domains, all of which are required for selective autophagy. WDFY-3 also contains a large N-terminal region that is relatively uncharacterized. Currently, wdfy-3(ok912) is the only mutant allele that has been characterized for this gene. This allele features a small deletion that is predicted to disrupt the C-terminal region of the protein. Here, we used CRISPR Cas9 to produce a new wdfy-3(cue30) allele that is a near complete deletion of the coding region. We report that, unlike the existing wdfy-3(ok912) allele, this new wdfy-3(cue30) null allele causes a weak overextension phenotype in the PLM axon. Like the existing wdfy-3(ok912) allele, the new wdfy-3(cue30) null allele can suppress PLM axon termination defects caused by an fsn-1 null allele. Creating and characterizing new wdfy-3 alleles will increase our understanding of this gene and could help elucidate more of the gene's conserved functions.

Patient comprehension of breast pathology report terminology: The need for patient-centered resources.

BACKGROUND: As health care continues to evolve toward information transparency, an increasing number of patients have access to their medical records, including result reports that were not originally designed to be patient-facing. Previous studies have demonstrated that patients have poor understanding of medical terminology. However, patient comprehension of terminology specific to breast pathology reports has not been well studied. We assessed patient understanding of common medical terms found in breast pathology reports. METHODS: A survey was administered electronically to patients scheduled for a screening mammogram within a multisite health care system. Participants were asked to objectively define and interpret 8 medical terms common to breast biopsy pathology reports. Patient perception of the utility of various educational tools was also assessed. Demographic information including health literacy, education level, previous cancer diagnosis, and primary language was collected. RESULTS: In total, 527 patients completed the survey. Terms including "malignant" and "benign" were the most correctly defined at 80% and 73%, respectively, whereas only 1% correctly defined "high grade." Factors including race/ethnicity and education level were correlated with more correct scores. Patients preferred educational tools that were specific to their diagnosis and available at the time they were reviewing their results. CONCLUSION: Patient comprehension of common medical terminology is poor. Potential assumptions of understanding based on patient factors including education, past medical history, and occupation are misinformed. With the newly mandated immediate release of information to patients, there is a pressing need to develop and integrate educational tools to support patients through all aspects of their care.

An autism-associated calcium channel variant causes defects in neuronal polarity in the ALM neuron of C. elegans.

Variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including bipolar disorder, schizophrenia, and ADHD. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. In our previous work, we demonstrated that an egl-19(gof) mutation, which is equivalent to the Timothy syndrome mutation in CACNA1C, can disrupt termination of the PLM axon in C. elegans. Here, we report a novel phenotype for the egl-19(gof) mutation, whereby it causes the growth of an ectopic process from the ALM cell body. We also extend our previous results to show that the egl-19(gof) mutation causes axon termination defects not only in the PLM axon, but also in the ALM axon. These results suggest that the Timothy syndrome mutation can disrupt multiple steps of axon development. Further work exploring the molecular mechanisms that underlie these perturbations in neuronal polarity and axon termination will give us better understanding of how variants in CACNA1C contribute to the axonal defects that underlie autism.

A National Survey of Motor Vehicle Crashes Among General Surgery Residents.

OBJECTIVES: Evaluate the frequency of self-reported, post-call hazardous driving events in a national cohort of general surgery residents and determine the associations between duty hour policy violations, psychiatric well-being, and hazardous driving events. SUMMARY OF BACKGROUND DATA: MVCs are a leading cause of resident mortality. Extended work shifts and poor psychiatric well-being are risk factors for MVCs, placing general surgery residents at risk. METHODS: General surgery residents from US programs were surveyed after the 2017 American Board of Surgery In-Training Examination. Outcomes included self-reported nodding off while driving, near-miss MVCs, and MVCs. Group-adjusted cluster Chi-square and hierarchical regression models with program-level intercepts measured associations between resident- and program-level factors and outcomes. RESULTS: Among 7391 general surgery residents from 260 programs (response rate 99.3%), 34.7% reported nodding off while driving, 26.6% a near-miss MVC, and 5.0% an MVC over the preceding 6 months. More frequent 80-hour rule violations were associated with all hazardous driving events: nodding off while driving {59.8% with ≥5 months with violations vs 27.2% with 0, adjusted odds ratio (AOR) 2.86 [95% confidence interval (CI) 2.21-3.69]}, near-miss MVCs, [53.6% vs 19.2%, AOR 3.28 (95% CI 2.53-4.24)], and MVCs [14.0% vs 3.5%, AOR 2.46 (95% CI 1.65-3.67)]. Similarly, poor psychiatric well-being was associated with all 3 outcomes [eg, 8.0% with poor psychiatric well-being reported MVCs vs 2.6% without, odds ratio 2.55 (95% CI 2.00-3.24)]. CONCLUSIONS: Hazardous driving events are prevalent among general surgery residents and associated with frequent duty hour violations and poor psychiatric well-being. Greater adherence to duty hour standards and efforts to improve well-being may improve driving safety.

Visual Experience-Dependent Oscillations and Underlying Circuit Connectivity Changes Are Impaired in Fmr1 KO Mice.

Fragile X syndrome (FX), the most common inherited form of autism and intellectual disability, is a condition associated with visual perceptual learning deficits. We recently discovered that perceptual experience can encode visual familiarity via persistent low-frequency oscillations in the mouse primary visual cortex (V1). Here, we combine this paradigm with a multifaceted experimental approach to identify neurophysiological impairments of these oscillations in FX mice. Extracellular recordings reveal shorter durations, lower power, and lower frequencies of peak oscillatory activity in FX mice. Directed information analysis of extracellularly recorded spikes reveals differences in functional connectivity from multiple layers in FX mice after the perceptual experience. Channelrhodopsin-2 assisted circuit mapping (CRACM) reveals increased synaptic strength from L5 pyramidal onto L4 fast-spiking cells after experience in wild-type (WT), but not FX, mice. These results suggest differential encoding of visual stimulus familiarity in FX via persistent oscillations and identify circuit connections that may underlie these changes.

Multi-institution Evaluation of Adherence to Comprehensive Postoperative VTE Chemoprophylaxis.

OBJECTIVES: The aims of this study were to: (1) measure the rate of failure to provide defect-free postoperative venous thromboembolism (VTE) chemoprophylaxis, (2) identify reasons for failure to provide defect-free VTE chemoprophylaxis, and (3) examine patient- and hospital-level factors associated with failure. SUMMARY BACKGROUND DATA: Current VTE quality measures are inadequate. VTE outcome measures are invalidated for interhospital comparison by surveillance bias. VTE process measures (e.g., SCIP-VTE-2) do not comprehensively capture failures throughout patients' entire hospitalization. METHODS: We examined adherence to a novel VTE chemoprophylaxis process measure in patients who underwent colectomies over 18 months at 36 hospitals in a statewide surgical collaborative. This measure assessed comprehensive VTE chemoprophylaxis during each patient's entire hospitalization, including reasons why chemoprophylaxis was not given. Associations of patient and hospital characteristics with measure failure were examined. RESULTS: The SCIP-VTE-2 hospital-level quality measure identified failures of VTE chemoprophylaxis in 0% to 3% of patients. Conversely, the novel measure unmasked failure to provide defect-free chemoprophylaxis in 18% (736/4086) of colectomies. Reasons for failure included medication not ordered (30.4%), patient refusal (30.3%), incorrect dosage/frequency (8.2%), and patient off-unit (3.4%). Patients were less likely to fail the chemoprophylaxis process measure if treated at nonsafety net hospitals (OR 0.62, 95% CI 0.39-0.99, P = 0.045) or Magnet designated hospitals (OR 0.45, 95% CI 0.29-0.71, P = 0.001). CONCLUSIONS: In contrast to SCIP-VTE-2, our novel quality measure unmasked VTE chemoprophylaxis failures in 18% of colectomies. Most failures were due to patient refusals or ordering errors. Hospitals should focus improvement efforts on ensuring patients receive VTE prophylaxis throughout their entire hospitalization.

An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.

Common and rare variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.