7 research outputs found
Autism traits in the RASopathies.
BackgroundMutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.MethodsWe examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).ResultsEach of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.ConclusionsHigher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs
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Autism traits in the RASopathies.
BackgroundMutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.MethodsWe examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).ResultsEach of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.ConclusionsHigher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs
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Clinical Markers Associated With Risk of Suicide or Drug Overdose Among Individuals With Smoking Exposure: A Longitudinal Follow-up Study of the COPDGene Cohort.
BACKGROUND: Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a spectrum of pulmonary diseases ranging from normal spirometry to severe COPD. RESEARCH QUESTION: Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study? STUDY DESIGN AND METHODS: We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV1 % predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk. RESULTS: The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV1 % predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio [HR], 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk. INTERPRETATION: In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function