Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias.

Polygenic risk scores (PRSs) are an important tool for understanding the role of common genetic variants in human disease. Standard best practices recommend that PRSs be analyzed in cohorts that are independent of the genome-wide association study (GWAS) used to derive the scores without sample overlap or relatedness between the two cohorts. However, identifying sample overlap and relatedness can be challenging in an era of GWASs performed by large biobanks and international research consortia. Although most genomics researchers are aware of best practices and theoretical concerns about sample overlap and relatedness between GWAS and PRS cohorts, the prevailing assumption is that the risk of bias is small for very large GWASs. Here, we present two real-world examples demonstrating that sample overlap and relatedness is not a minor or theoretical concern but an important potential source of bias in PRS studies. Using a recently developed statistical adjustment tool, we found that excluding overlapping and related samples was equal to or more powerful than adjusting for overlap bias. Our goal is to make genomics researchers aware of the magnitude of risk of bias from sample overlap and relatedness and to highlight the need for mitigation tools, including independent validation cohorts in PRS studies, continued development of statistical adjustment methods, and tools for researchers to test their cohorts for overlap and relatedness with GWAS cohorts without sharing individual-level data.

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture.

OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

SCN8A self-limited infantile epilepsy: Does epilepsy resolve?

SCN8A variants cause a spectrum of epilepsy phenotypes ranging from self-limited infantile epilepsy (SeLIE) to developmental and epileptic encephalopathy. SeLIE is an infantile onset focal epilepsy, occurring in developmentally normal infants, which often resolves by 3 years. Our aim was to ascertain when epilepsy resolves in SCN8A-SeLIE. We identified unpublished individuals with SCN8A-SeLIE and performed detailed phenotyping. Literature was searched for published SCN8A-SeLIE cases. Nine unpublished individuals from four families were identified (age at study = 3.5-66 years). Six had their last seizure after 3 years (range = 4-21 years); although drug-responsive and despite multiple weaning attempts (1-5), five of six remain on antiseizure medications (carbamazepine, n = 3; lamotrigine, n = 2). We identified 29 published individuals with SCN8A-SeLIE who had data on seizure progression. Of the 22 individuals aged at least 10 years, reported here or in the literature, nine of 22 (41%) had seizure offset prior to 3 years, five of 22 (23%) had seizure offset between 3 and 10 years, and eight of 22 (36%) had seizures after 10 years. Our data highlight that more than half of individuals with SCN8A-SeLIE continue to have seizures into late childhood. In contrast to SeLIE due to other etiologies, many individuals have a more persistent, albeit drug-responsive, form of epilepsy.

Increased paternal corticosterone exposure influences offspring behaviour and expression of urinary pheromones.

BACKGROUND: Studies have shown that paternal stress prior to conception can influence the innate behaviours of their offspring. The evolutionary impacts of such intergenerational effects are therefore of considerable interest. Our group previously showed in a model of daily stress that glucocorticoid treatment of adult male mouse breeders prior to conception leads to increased anxiety-related behaviours in male offspring. Here, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of progeny and its potential influence on reproductive success. RESULTS: We assessed social parameters including social reward, male attractiveness and social dominance, in the offspring (F1) and grand-offspring (F2). We report that paternal corticosterone treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional role in driving female attraction. We investigated the epigenetic regulation of major urinary protein (Mup) expression by performing the first Oxford Nanopore direct methylation of sperm DNA in a mouse model of stress, but found no differences in Mup genes that could be attributed to corticosterone-treatment. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in F1 offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. Interestingly, no phenotypic differences were observed in the F2 grand-offspring. CONCLUSIONS: Overall, our findings highlight the potential of moderate paternal stress to affect intergenerational (mal)adaptive responses, informing future studies of adaptiveness in rodents, humans and other species.

Research Protocol Adaptations During the COVID-19 Pandemic: A Process Evaluation.

In general, COVID-19-related adaptations that transitioned in-person assessments and interventions to a virtual format were not routinely evaluated. We aimed to conduct a process evaluation to examine the impact of COVID-19-related adaptations on a behavior change intervention designed to increase exercise adherence among Veterans with mobility difficulty. We used secondary data from a nonrandomized study to complete a process evaluation examining the intervention's reach, recruitment, fidelity, dose delivered by physical therapists, and the dose received by the 14 participating Veterans. The physical therapist delivered 95% (133/140) of the study's 10 sessions. Sessions with the lowest delivery dose included Sessions 1 and 10 (86%; n = 12/14). The elements with the lowest dose received included using an exercise journal and developing a postintervention plan (86%; n = 12/14). Our COVID-19 adaptations allowed us to provide our intervention to the majority (67%) of eligible participants without a negative impact on fidelity, dose delivered, or dose received.

Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation.

PURPOSE: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. METHODS: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. RESULTS: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. CONCLUSION: The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

Feasibility and Preliminary Efficacy of Virtual Rehabilitation for Middle and Older Aged Veterans With Mobility Limitations: A Pilot Study.

Objective: To evaluate the feasibility and preliminary efficacy of the transition of an outpatient center-based rehabilitation program for middle and older aged Veterans with mobility limitations to a tele-health platform. Design: Non-randomized non-controlled pilot study including 10 treatment sessions over 8 weeks and assessments at baseline, 8, 16, and 24 weeks. Setting: VA Boston Healthcare System ambulatory care between August 2020 and March 2021. Participants: Veterans aged 50 years and older (n=178) were contacted via letter to participate, and 21 enrolled in the study. Intervention: Participants had virtual intervention sessions with a physical therapist who addressed impairments linked to mobility decline and a coaching program promoting exercise adherence. Main Outcome Measures: Ambulatory Measure for Post-Acute Care (AM-PAC), Phone-FITT, and Self-Efficacy for Exercise (SEE) scale. Results: Completers (n=14, mean age 74.9 years, 86% men) averaged 9.8 out of 10 visits. Changes in the Ambulatory Measure for Post-Acute Care (AM-PAC) exceeded clinically meaningful change after 8 and 24 weeks of treatment, at 4.1 units and 4.3 units respectively. Statistically significant improvements from baseline in AM-PAC and Phone-FITT were observed after 8 weeks of treatment and at 24 weeks. No significant changes were observed in exercise self-efficacy. Conclusions: In this group of veterans, telerehab was feasible and demonstrated preliminary efficacy in both mobility and physical activity, thus justifying further investigation in a larger scale clinical trial.

An innovative rehabilitation program for the veterans affairs post-acute skilled nursing setting: Preliminary results.

BACKGROUND: Skilled nursing rehabilitative care plays a critical role in older adults' functional recovery impacting post-discharge outcomes. Variations across post-acute rehabilitative care services and patient outcomes indicate a need to improve rehabilitative care in this setting. We adapted a successful outpatient care program (Live Long Walk Strong-LLWS) to address this need in post-acute care settings within the Veterans Health Administration. LLWS differs from standard PT care by treating impairments linked to functional decline that are not traditionally targeted by standard care, providing formalized coaching to optimize behavior change, and providing post-discharge case management to optimize long-term outcomes. The purpose was to adapt, refine and implement the LLWS program for the Community Living Center (CLC), determine its acceptability and feasibility, and evaluate its preliminary effectiveness among older adults. METHODS: The design of the program was adapted from the original outpatient LLWS program to the CLC setting through quality improvement methods and the Replicating Effective Programs (REP) framework. Primary outcomes included measures of feasibility and acceptability of >80% enrollment and completion of sessions as well as preliminary effectiveness using performance-based and patient-reported measures of function including the Short Physical Performance Battery (SPPB), AM-PAC, a Global Rating of Change questionnaire, and a satisfaction survey. RESULTS: After 18 months, 51 Veterans had enrolled in the LLWS program, with 94.1% maintaining enrollment. We observed >80% completion of the inpatient and home follow-up sessions. Most patients were highly satisfied with care. Improvements in the SPPB (2.3 (SD 2.2) points), gait speed (0.17 (0.14) m/s) and the AM-PAC (6.5 (SD 5.7)) surpassed clinically meaningful thresholds. CONCLUSIONS: This novel care program is feasible and acceptable to Veterans, demonstrating preliminary effectiveness with improving functional outcomes. Future research is needed to further examine the program's impact on other important outcomes relative to standard modes of care.

The Association Between Severity of Radiographic Knee OA and Recurrent Falls in Middle and Older Aged Adults: The Osteoarthritis Initiative.

BACKGROUND: Knee osteoarthritis (KOA) is the most prevalent type of OA and a leading cause of disability in the United States. Falls are a major public health concern in older adults. Our aim was to examine how the severity of radiographic KOA affects recurrent falls in a cohort of middle-aged and older individuals enrolled in the Osteoarthritis Initiative. METHODS: About 3 972 participants, mean age of 63 years, 58% female were included. Participants were divided into 5 mutually exclusive groups based on their worst Kellgren-Lawrence grade of radiographic KOA from annual x-rays from baseline to 36 months. Generalized estimating equations for repeated logistic regression were used to model the association between KOA severity and the likelihood of recurrent falls (≥2 falls/year) over 5 years of follow-up (>36 to 96 months). RESULTS: Older adults (≥age 65) with KOA were at higher odds of recurrent falls in comparison to individuals without KOA in multivariate models (possible OA odds ratio [OR] = 2.22, 95% CI = 1.09-4.52; mild OA OR = 2.48, 95% CI = 1.34-4.62; unilateral moderate-severe OA OR = 2.84, 95% CI = 1.47-5.50; bilateral moderate-severe OA OR = 2.52, 95% CI = 1.13-5.62). Middle-aged adults (aged 45-64) with KOA did not have increased odds of recurrent falls in comparison to those without KOA except for possible KOA (OR = 1.86, 95% CI = 1.01-2.78; KOA severity × Age interaction = 0.025). CONCLUSION: Older adults with radiographic evidence of KOA have an increased likelihood of experiencing recurrent falls in comparison to those without KOA independent of established risk factors. Our results suggest that fall prevention efforts should include older adults with all stages of KOA.

Examining physical activity participation barriers among adults 50 years and older: a scoping review.

Background: Addressing physical activity (PA) barriers is essential for increasing PA levels in middle-aged and older adults. However, there are no recommendations on selecting PA barrier assessment tools. Objectives: Thus, we aimed to identify and provide clinimetric properties on PA barrier assessment tools that healthcare providers, exercise experts, and public health officials can use to examine potential barriers faced by community-dwelling adults 50 years and older. Methods: We performed a systematic search of the following databases: PubMed, PsycINFO, CINAHL, and Web of Science. Articles were included if they presented clinimetric data on a PA participation barrier assessment tool for community-dwelling participants with a mean age of 50 years and older. The 561 identified articles underwent multiple rounds of blinded reviews. Included articles underwent data extraction for participant characteristics, scoring, constructs, reference tests, and clinimetric properties. Results: The 35 included articles reported on 33 different PA participation barrier assessment tools. Eighteen articles reported on participants with cardiovascular, musculoskeletal, or neurological diagnoses, diabetes, hemodialysis, history of cancer, or mobility limitations. Tools with two or more supporting publications included the Exercise Benefits/Barrier Scale (EBBS), Episode-Specific Interpretations of Exercise Inventory (ESIE), and Inventory of Physical Activity and Barriers (IPAB). Due to differences in methodologies, across-tool comparison was not possible. Conclusion: The EBBS, ESIE, and IPAB are promising tools for community-dwelling adults 50 years and older. However, additional research is warranted to identify the best PA barrier assessment tool among adults 50 years and older.

The Live Long Walk Strong Rehabilitation Program Study: Design and Methods.

Objective: To identify attributes targeted by rehabilitative treatment within which improvements lead to short- and long-term changes in mobility. Maintaining independence in mobility is important to many older adults and is associated with critical outcomes such as aging in place, morbidity, and mortality. Design: The Live Long Walk Strong rehabilitation study is a phase 2 single-blind, randomized controlled trial. Setting: Veterans Affairs Boston Healthcare System, outpatient physical therapy. Participants: 198 community-dwelling middle- and older-aged veterans (aged 50 years and older) will be recruited from primary care practices (N=198). Interventions: Comparing a moderate-vigorous intensity physical therapy program of 10 sessions with a waitlist control group. Main Outcome Measure: The primary outcome measure is gait speed. Secondary outcomes include leg strength and power, trunk muscle endurance, gait smoothness, and exercise self-efficacy. Results: Outcomes will be assessed within 2 weeks of intervention completion, at 8 weeks postintervention, and at 16 weeks postintervention. Two-sample t tests will compare mean change in gait speed and target attributes (leg power, trunk muscle endurance, gait smoothness, and exercise self-efficacy) between treatment and control groups. Paired t tests will examine within-person change at subsequent follow-up visits. Multivariable regression analyses will evaluate relationships between dependent and independent variables and potential mediation adjusting for relevant covariates. Conclusions: Results of this study are expected to advance and refine the design of Live Long Walk Strong rehabilitative care and demonstrate its proof of concept and efficacy.

Examining physical activity participation barriers among adults 50 years and older: a scoping review protocol.

Background: Despite the benefits of physical activity (PA), 61% of adults 50 years and older do not meet the recommended levels of PA. One method of increasing PA participation is assessing and addressing PA participation barriers. Currently, no guidance on methodologies for assessing PA participation barriers exist. Objective: The primary objective of this scoping review is to map the methodologies used to examine potential PA participation barriers faced by community-dwelling adults 50 years and older. A secondary objective is to evaluate the clinimetric properties of these methodologies. Methods: This scoping review protocol is registered with Open Science Framework (https://osf.io/wd2hx). A systematic search of the following databases will be performed: PubMed, PsycINFO, CINAHL, Web of Science, and PEDro. Included studies will 1) present either a) data on development or clinimetric properties of PA participation barrier tool (s); or b) relative risk or odds ratios of PA participation barrier(s); 2) compare PA participation barriers or PA participation barrier tool(s) to either subjective or objective measures of PA; and 3) comprise of community-dwelling participants with a mean age of 50 years and older. A two-phase blinded independent screening process will be conducted to select the included publications. Data will be extracted using a standardized form and cross-checked by the first author. A narrative summary will accompany the results presented in tables and figures. Conclusion: This scoping review will provide a comprehensive understanding of current literature and gaps related to PA participation barrier methodologies used with adults 50 years and older.

Development of a Coaching Protocol to Enhance Self-efficacy Within Outpatient Physical Therapy.

Objective: To describe the development of the Specific, Measurable, Action-Oriented, Realistic, and Timed (SMART) Coaching Protocol to increase exercise self-efficacy in middle-aged and older adults participating in Live Long Walk Strong (LLWS) Rehabilitation Program. LLWS Rehabilitation Program is an innovative physical therapist (PT) delivered outpatient intervention for middle- and older-aged adults with slow gait speed. Design: Phase II randomized controlled trial (RCT) with masked outcome assessment. We applied the Knowledge to Action Framework to develop and implement the LLWS SMART Coaching Protocol within an RCT for the LLWS Rehabilitation Program. Data will be collected at baseline and post intervention at 2, 8 and 16 weeks. Setting: Outpatient; VA Boston Healthcare System. Participants: Community-dwelling veterans (N=198) (older than 50 years) with slow gait speed (<1.0 m/s). Interventions: Participants will be randomized to the LLWS Rehabilitation Program, an 8-week (10-session) PT-delivered intervention, or wait-list control group. Each study visit will introduce a new SMART Coaching module focused on goal setting, exercise adherence, and addressing internal and external barriers to meeting exercise goals. Main Outcome Measures: Primary outcome is gait speed and secondary outcome is the Self-Efficacy for Exercise Scale. Conclusions: Incorporating cognitive behavioral tools in physical therapy intervention research is critical for targeting motivational processes needed for exercise behavior change.

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

BACKGROUND: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies. METHODS: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. FINDINGS: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. INTERPRETATION: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology. FUNDING: National Health and Medical Research Council of Australia, National Institutes of Health, American Academy of Neurology, Thomas B and Jeannette E Laws McCabe Fund, Mirowski Family Foundation.

Reliability of Virtual Physical Performance Assessments in Veterans During the COVID-19 Pandemic.

OBJECTIVE: To determine the reliability of 3 physical performance tests performed via a telehealth visit (30-s arm curls test, 30-s chair stand test, 2-min step test) among community-dwelling older veterans. DESIGN: Cross sectional study. SETTING: Virtual. PARTICIPANTS: Veterans (N=55; mean age 75y) who enrolled in Gerofit, a virtual group exercise program. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were tested by 2 different assessors at 1 time point. The intraclass correlation coefficient (ICC) with 95% confidence intervals and Bland-Altman plots were used as measures of reliability. To assess generalizability, ICCs were further evaluated by health conditions (type 2 diabetes, arthritis, obesity, depression). RESULTS: Assessments were conducted among 55 participants. The ICC was above 0.98 for all 3 tests across health conditions and Bland-Altman plots indicated that there were no significant systematic errors in the measurement. CONCLUSIONS: The virtual physical performance measures appear to have high reliability and the findings are generalizable across health conditions among veterans. Thus, they are reliable for evaluating physical performance in older veterans in virtual settings.

Evaluating the Feasibility and Effects of a Short-Term Task Specific Power Training With and Without Cognitive Training Among Older Adults With Slow Gait Speed: A Pilot Study.

OBJECTIVE: To investigate the feasibility and efficacy of short-term functional power training and further examine whether the addition of cognitive training targeting sustained attention and inhibitory control would augment the effect on the outcomes. DESIGN: Randomized pilot study. SETTING: Clinical research facility. PARTICIPANTS: Community-dwelling primary care patients (N=25) aged >65 years with mobility limitation within the VA Boston Healthcare System. INTERVENTIONS: Participants were randomly assigned to either functional power training (n=14) or functional power+cognitive training (n=11), offered 3 times a week for 6 weeks. Session durations were either 70 minutes (functional power+cognitive training) or 40 minutes (functional power training). MAIN OUTCOME MEASURES: We evaluated feasibility (dropouts, attendance), mobility performance (Short Physical Performance Battery [SPPB]), leg power [stair climb test]), dynamic balance [figure-of-8], and gait characteristics [gait speed, stance time, step width, swing time, step length, variabilities under single-task and dual-task conditions]). Nonparametric analyses were used to compare overall pre-post changes and between-group differences. RESULTS: Of the 39 veterans screened, 25 were randomized and enrolled. Twenty-one men with a mean age 76±7 years completed the study; 86% were white. Participants had a mean SPPB score of 8.3±1.6 out of 12. For those completing the study, overall attendance was 79%. Among all participants, clinically relevant and/or statistically significant median change in mobility performance (∆1 point), leg power (∆25.0W), dynamic balance (∆-1.1s), and gait characteristics (gait speed [∆0.08s, ∆0.09s], step length [∆1.9cm, ∆3.8cm], and stance time [∆-0.02s, ∆-0.05s] under single- and dual-task, respectively) were observed after 6 weeks of training. There were no statistically significant group differences in dropouts, attendance rate, or any of the outcomes based on cognitive training status. CONCLUSIONS: Short-term functional power training with or without a cognitive training led to clinically meaningful improvements in mobility performance, leg power, dynamic balance, and gait characteristics. These findings add to the body of evidence supporting the benefits of functional power training on clinically relevant outcomes. Additional cognitive training did not have an added effect on the study outcomes from our study. Further research is needed.

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome.

Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all individuals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G > T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippocampal sclerosis.

Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus.

OBJECTIVE: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. METHODS: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. RESULTS: Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). CONCLUSION: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.

PTSD Improvement Associated with Social Connectedness in Gerofit Veterans Exercise Program.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is common in Veterans. Symptoms can perpetuate into late life, negatively impacting physical and mental health. Exercise and social support are beneficial in treating anxiety disorders such as PTSD in the general population, although less is known about the impact on Veterans who have lived with PTSD for decades. This study assessed associations between social connectedness, physical function and self-reported change in PTSD symptoms among older Veterans specifically participating in Gerofit. DESIGN: Prospective clinical intervention. SETTING: Twelve sites of Veterans Affairs (VA) Gerofit exercise program across the United States. PARTICIPANTS: Three hundred and twenty one older Veteran Gerofit participants (mean age = 74) completed physical assessments and questionnaires regarding physical and emotional symptoms and their experience. MEASUREMENTS: Measures of physical function, including 30-second chair stands, 10-m and 6-min walk were assessed at baseline and 3 months; change in PTSD symptoms based on the Diagnostic Statistical Manual-5 (DSM-5) assessed by a self-report questionnaire; and social connection measured by the Relatedness Subscale of the Psychological Need Satisfaction in Exercise scale (PNSE) were evaluated after 3 months of participation in Gerofit. RESULTS: Ninety five (29.6%) Veterans reported PTSD. Significant improvement was noted in self-rated PTSD symptoms at 3 months (P < .05). Moderate correlation (r = .44) was found between social connectedness with other participants in Gerofit and PTSD symptom improvement for those Veterans who endorsed improvement (n = 59). All participants improved on measures of physical function. In Veterans who endorsed PTSD there were no significant associations between physical function improvement and PTSD symptoms. CONCLUSION: Veterans with PTSD that participated in Gerofit group exercise reported symptom improvement, and social connectedness was significantly associated with this improvement. In addition to physical health benefits, the social context of Gerofit may offer a potential resource for improving PTSD symptoms in older Veterans that warrants further study.