Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.

The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.

PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.

Patients benefit from mentoring students in an interprofessional health mentors program: A contextual-developmental analysis.

PURPOSE: Mentorship programs in health professional education are often characterized as a mutually beneficial relationship between mentor and mentee, but little is known about benefits for mentors. Mentors can be health professionals, academic faculty, other students (peers), and patients (health mentors). We studied the benefits that health mentors (people with chronic health conditions or disabilities, or a caregiver) get from mentoring students, and the contextual factors that contribute to, or explain these benefits. METHODS: We surveyed 72 health mentors who had mentored between one and eight cohorts of students from different health professions in the health mentors program at the University of British Columbia. Using a contextual-developmental framework of mentorship, we analyzed mentors' responses to open-ended questions about how they benefit from the program. RESULTS: Benefits fit into three categories: generativity (guiding the next generation), transformation (personal growth and reflection), and 'career' development (new activities resulting from increased self-efficacy). Contextual factors that contributed to benefits included the non-clinical setting, informality of meetings and reciprocal learning, and feeling valued by the program and students. CONCLUSIONS: Health mentors perceive benefits in passing on their lived experiences to students, leading to personal growth and new activities. Their perspectives offer unique insights into the workings of effective mentorship relationships. There is much to be learned about how benefits of mentoring are linked to program design.

Mesenteric cysts, lymphatic leak, and cerebral cavernous malformation in a proband with KRIT1-related disease.

Cerebral cavernous malformations (CCMs) of the central nervous system arise sporadically or secondary to genomic variation. Established genetic etiologies include deleterious variants in KRIT1 (CCM1), malcavernin (CCM2), and PDCD10 (CCM3). KRIT1-related disease has not been described in conjunction with lymphatic defects, although lymphatic defects with abnormal endothelial cell junctions have been observed in mice deficient in HEG1-KRIT1 signaling. We report a proband with CCMs, multiple chylous mesenteric cysts, and chylous ascites with leaky lymphatic vasculature. Clinical short-read exome sequencing detected a disease-associated KRIT1 variant (NM_194456.1:c.[1927C>T];[=], p.(Gln643*)). We postulate an expansion of KRIT1-related disease to include lymphatic malformations and lymphatic endothelial dysfunction.

The practice of genomic medicine: A delineation of the process and its governing principles.

Genomic medicine, an emerging medical discipline, applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling widespread adoption and integration of genomic medicine into clinical practice is key to achieving precision medicine. We delineate a biological framework defining diagnostic utility of genomic testing and map the process of genomic medicine to inform integration into clinical practice. This process leverages collaboration and collective cognition of patients, principal care providers, clinical genomic specialists, laboratory geneticists, and payers. We detail considerations for referral, triage, patient intake, phenotyping, testing eligibility, variant analysis and interpretation, counseling, and management within the utilitarian limitations of health care systems. To reduce barriers for clinician engagement in genomic medicine, we provide several decision-making frameworks and tools and describe the implementation of the proposed workflow in a prototyped electronic platform that facilitates genomic care. Finally, we discuss a vision for the future of genomic medicine and comment on areas for continued efforts.

The Use of Stimulant Medication to Treat Attention-Deficit/Hyperactivity Disorder in Elite Athletes: A Performance and Health Perspective.

The use of stimulants as a treatment for attention-deficit/hyperactivity disorder (ADHD) among elite athletes is a controversial area with some arguing that stimulant use should not be permitted because it offers an advantage to athletes (fair play perspective). Guided by an integrated model of athletic performance, we address common concerns raised about stimulant use in sports from our perspective, which we coined the "performance and health perspective," highlighting relevant research and pointing to gaps in empirical research that should be addressed before bans on use of stimulants for athletes with ADHD are considered. The current article posits that a stimulant ban for athletes with ADHD does not necessarily facilitate fair play, ensure safety, or align with existing policies of large governing bodies. Instead, we recommend that stimulant medication be allowed in high-level sport, following proper diagnosis by a trained professional and a cardiac assessment to confirm no underlying heart conditions. Athletes with ADHD approved to use stimulant medication should be monitored by a health care professional, physically reevaluated and reassessed for ADHD as clinically appropriate and as indicated by relevant sports governing bodies. This performance and health perspective is consistent with that of multiple sport governing bodies who offer therapeutic use.

Effect of sleep extension on sluggish cognitive tempo symptoms and driving behavior in adolescents with chronic short sleep.

OBJECTIVE/BACKGROUND: Few adolescents report obtaining adequate amounts of sleep. Correlational studies have linked adolescent short sleep with driving crashes and sluggish cognitive tempo (SCT), a cluster of symptoms that include sluggishness and low persistence that are related to but distinct from inattention and sleepiness. The relationship between SCT and driving is understudied, and no study has experimentally examined the relationship between SCT and sleep. We examined the relationship between SCT and driving problems in a sample of chronically short-sleeping adolescents. We also examined whether experimentally extending sleep improved SCT and driving behaviors. PARTICIPANTS/METHODS: Licensed 16- to 18-year-old adolescents who regularly obtained five to seven hours of sleep completed a five-week at-home experimental protocol: a baseline week to determine typical sleep (TYP), followed in a counterbalanced order by two-week spans in which school-night bedtimes and rise times were (a) matched to TYP or (b) modified to extend (EXT) time in bed by 1.5 h/night. Sleep was monitored by actigraphy. Self- and parent-reported SCT and inattention and self-reported driving problems were recorded at baseline and following each condition. Of the 38 eligible participants who completed the baseline session, 24 completed all five weeks of the protocol. RESULTS: After controlling for inattention, only parent-reported SCT was significantly positively associated with self-reported purposeful driving violations at baseline. Adolescents reported lesser SCT during EXT than during TYP. Further, after controlling for inattention, participants who reported improvement in SCT demonstrated fewer driving problems during EXT than during TYP. CONCLUSIONS: Preliminary findings suggest that extending sleep in short-sleeping adolescents may help alleviate SCT symptoms and improve driving.

Does fair play reduce concussions? A prospective, comparative analysis of competitive youth hockey tournaments.

BACKGROUND/AIM: To determine if Boys Bantam and Peewee and Girls U14 sustain fewer concussions, head hits, 'other injuries' and penalties in hockey tournaments governed by intensified fair play (IFP) than non-intensified fair play (NIFP). METHODS: A prospective comparison of IFP, a behaviour modification programme that promotes sportsmanship, versus control (non-intensified, NIFP) effects on numbers of diagnosed concussions, head hits without diagnosed concussion (HHWDC), 'other injuries', number of penalties and fair play points (FPPs). 1514 players, ages 11-14 years, in 6 IFP (N=950) and 5 NIFP (N=564) tournaments were studied. RESULTS: Two diagnosed concussions, four HHWDC, and six 'other injuries' occurred in IFP tournaments compared to one concussion, eight HHWDC and five 'other injuries' in NIFP. There were significantly fewer HHWDC in IFP than NIFP (p=0.018). However, diagnosed concussions, 'other injuries', penalties and FPPs did not differ significantly between conditions. In IFP, a minority of teams forfeited the majority of FPPs. Most diagnosed concussions, HHWDC, and other injuries occurred to Bantam B players and usually in penalised teams that forfeited their FPPs. CONCLUSIONS: In response to significant differences in HHWDC between IFP and NIFP tournaments, the following considerations are encouraged: mandatory implementation of fair play in regular season and tournaments, empowering tournament directors to not accept heavily penalised teams, and introducing 'no body checking' in Bantam.

Impact of transfer distance and time on rural brain injury outcomes.

OBJECTIVES: After rural injury, evaluation at local hospitals with transfer to regional trauma centres may delay definitive care. This study sought to determine the impact of such delays on outcomes in patients with TBI within a mature regional trauma system. METHODS: The ETMC Level 1 Trauma registry was queried from 2008-2013 for patients with blunt TBI, aged ≥ 18 and admitted ≤ 24 hours from injury and stratified them as 'transfer' vs 'direct' admission. Demographics, transfer distance, transfer times and outcomes were compared using Chi-square, t-test and multivariable logistic regression; p < 0.05 was significant. RESULTS: During the study period, 1845 patients met inclusion criteria: 947 'direct' and 898 'transfers'. For transfers, median distance was 60.1 miles; mean time to initial care was 1.2 ± 2.7 hours and time to Level 1 care was 5.0 ± 2.4 hours. Transfer patients were older (56 vs 49 years; p < 0.01) and had more comorbidities, but had lower mean ISS (15.9 vs 18.8; p < 0.01) and lower mortality (7.0 vs 10.3%; p < 0.03), complications and LOS. Neurosurgical intervention was comparable (p = 0.88), as was mortality for patients with ISS ≥ 15 (12.4% vs 14.8%; p = 0.28). After regression analysis, advanced age and increasing ISS, not distance or time, predicted mortality. CONCLUSION: Neither transfer distance nor time independently contributed to mortality for TBI after rural injury. An established regional trauma system, with initial local stabilization using ATLS principles, may help reduce negative outcomes for injured patients in rural settings.