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2.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

4.
Genet Med ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30245510

RESUMO

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

5.
Clin Endocrinol (Oxf) ; 89(5): 596-604, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30099760

RESUMO

OBJECTIVE: We assessed body composition, bone mineral density (BMD), glucose and lipids in Williams syndrome (WS), a rare microdeletion disorder. DESIGN: Individuals with WS had outpatient assessment at Massachusetts General Hospital. Controls were selected from the National Health and Nutrition Examination Survey (NHANES 2005-2006). PATIENTS: A total of 22 individuals with WS, each matched by age, sex and race to four NHANES controls. MEASUREMENTS: Blood sampling, oral glucose tolerance test, dual-energy X-ray absorptiometry scan. RESULTS: WS and control groups were 59% female and 29 ± 8 years old. Compared to controls, individuals with WS were shorter but had similar body weight, with more fat and less lean mass. Per cent body fat was higher in WS even after adjusting for BMI (+2.1% [95% CI 0.4, 3.9%]). Four WS patients had abnormal lower extremity fat accumulation resembling lipedema. HbA1c (+0.5% [0.2, 0.7]) and 2-hour glucose (+68 mg/dL [44, 93]) were higher in WS vs controls, differences which persisted after adjusting for BMI. Fasting glucose was comparable between groups. LDL (-18 mg/dL [-35, -2]) and triglycerides (-45 mg/dL [-87, -2]) were significantly lower in WS. Whole-body BMD was significantly lower (-0.15 g/cm2 [-0.20, -0.11]) in WS, and this remained true controlling for height (-0.06 g/cm2 [-0.11, -0.02]). Vitamin D was <30 ng/mL in 81% of those with WS. CONCLUSIONS: On average, adults with WS have increased fat, decreased lean mass, impaired glucose homeostasis and reduced BMD. Clinical efforts to build muscle and bone mass, and to ensure vitamin D sufficiency, are warranted. Genotype-phenotype research efforts are also warranted.

6.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

7.
J Autism Dev Disord ; 48(3): 947-952, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29164439

RESUMO

Descriptions of individuals with Williams syndrome (WS) and co-morbid major depressive disorder (MDD) with psychotic features have not appeared in the literature. In addition to reviewing previous reports of psychotic symptoms in persons with WS, this paper introduces clinical histories and therapeutic management strategies for three previously unreported adults with WS diagnosed with co-morbid MDD with psychotic features. Co-morbid medical disorders common in WS are highlighted with regard to safe and appropriate pharmacological treatment. The importance of assessment for co-morbid MDD with psychotic features in individuals with WS is emphasized.

9.
J Pediatr ; 178: 254-260.e4, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27574996

RESUMO

OBJECTIVE: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.


Assuntos
Cálcio/sangue , Hipercalcemia/complicações , Síndrome de Williams/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Hipercalcemia/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
Am J Med Genet A ; 164A(9): 2217-25, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24920525

RESUMO

Previous examination in a small number of individuals with Williams syndrome (also referred to as Williams-Beuren syndrome) has shown subtly softer skin and reduced deposition of elastin, an elastic matrix protein important in tissue recoil. No quantitative information about skin elasticity in individuals with Williams syndrome is available; nor has there been a complete report of dermatologic findings in this population. To fill this knowledge gap, 94 patients with Williams syndrome aged 7-50 years were recruited as part of the skin and vascular elasticity (WS-SAVE) study. They underwent either a clinical dermatologic assessment by trained dermatologists (2010 WSA family meeting) or measurement of biomechanical properties of the skin with the DermaLab™ suction cup (2012 WSA family meeting). Clinical assessment confirmed that soft skin is common in this population (83%), as is premature graying of the hair (80% of those 20 years or older), while wrinkles (92%), and abnormal scarring (33%) were detected in larger than expected proportions. Biomechanical studies detected statistically significant differences in dP (the pressure required to lift the skin), dT (the time required to raise the skin through a prescribed gradient), VE (viscoelasticity), and E (Young's modulus) relative to matched controls. The RT (retraction time) also trended longer but was not significant. The biomechanical differences noted in these patients did not correlate with the presence of vascular defects also attributable to elastin insufficiency (vascular stiffness, hypertension, and arterial stenosis) suggesting the presence of tissue specific modifiers that modulate the impact of elastin insufficiency in each tissue.


Assuntos
Pele/patologia , Síndrome de Williams/patologia , Adolescente , Adulto , Fenômenos Biomecânicos , Estudos de Casos e Controles , Criança , Estudos de Coortes , Demografia , Família , Cor de Cabelo , Humanos , Pessoa de Meia-Idade , Pele/fisiopatologia , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia , Síndrome de Williams/fisiopatologia
11.
J Child Neurol ; 29(11): NP135-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24396132

RESUMO

Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described.


Assuntos
Acetilcisteína/uso terapêutico , Psicotrópicos/uso terapêutico , Síndrome de Williams/tratamento farmacológico , Síndrome de Williams/psicologia , Feminino , Humanos , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Adulto Jovem
12.
Hypertension ; 63(1): 74-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24126171

RESUMO

Williams syndrome is caused by the deletion of 26 to 28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln(+/-) mouse suggests that affected people may also have stiff vasculature, a risk factor for stroke, myocardial infarction, and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case-control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (P<0.001), with increased stiffness observed in even the youngest children with Williams syndrome. Pulse wave velocity increased with age at comparable rates in cases and controls, and although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of antihypertensive medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with antihypertensives or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive.


Assuntos
Dosagem de Genes , Hipertensão/genética , NADPH Oxidases/genética , Rigidez Vascular/genética , Síndrome de Williams/genética , Adolescente , Adulto , Anti-Hipertensivos/uso terapêutico , Estudos de Casos e Controles , Criança , Humanos , Hipertensão/tratamento farmacológico , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Fenótipo , Análise de Onda de Pulso , Adulto Jovem
13.
Am J Med Genet A ; 161A(3): 534-41, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401422

RESUMO

Healthcare providers often share difficult or life-altering news with their patients yet this challenging and delicate process is frequently met with dissatisfaction by those receiving this news. Articles and guidelines exist to aid providers in sharing diagnoses such as Down syndrome, but relatively few have focused on rare genetic conditions often diagnosed years after birth. For this reason, we sought to learn about the experience of receiving a diagnosis from parents of children with Williams syndrome. We asked members of the Williams Syndrome Association to complete an anonymous online survey about recollections related to the diagnostic process. Responses, both close-ended and open-ended, were received from 600 families across the United States. Analysis revealed a high proportion of families (59.91%) with at least some negative recollections about the experience (and nearly half of those with negative recollections denied recalling anything positive). Factors influencing a more positive overall perception of the experience included receiving written information about Williams syndrome and seeing a genetic counselor. Analysis of open-ended responses identified additional positive and negative themes; for example, nearly one quarter of respondents expressed a desire to be given hope when receiving the diagnosis. Based on these analyses, we offer several specific recommendations for improving the diagnostic process in the future.


Assuntos
Pais/psicologia , Revelação da Verdade , Síndrome de Williams/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Crianças com Deficiência , Emoções Manifestas , Aconselhamento Genético , Pesquisas sobre Serviços de Saúde , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Preferência do Paciente , Percepção , Relações Profissional-Paciente , Estados Unidos , Adulto Jovem
14.
Diabetes Care ; 36(1): 13-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22933432

RESUMO

OBJECTIVE: To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS: We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants. RESULTS: The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m(2), with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison). CONCLUSIONS: Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Aconselhamento Genético , Idoso , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Sobrepeso
15.
J Genet Couns ; 21(5): 684-91, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22302620

RESUMO

Advances in genetic epidemiology have increased understanding of common, polygenic preventable diseases such as type 2 diabetes. As genetic risk testing based on this knowledge moves into clinical practice, we propose that genetic counselors will need to expand their roles and adapt traditional counseling techniques for this new patient set. In this paper, we present a genetic counseling intervention developed for a clinical trial [Genetic Counseling/Lifestyle Change for Diabetes Prevention, ClinicalTrials.gov identifier: NCT01034319] designed to motivate behavioral changes for diabetes prevention. Seventy-two phenotypically high-risk participants received counseling that included their diabetes genetic risk score, general education about diabetes risk factors, and encouragement to participate in a diabetes prevention program. Using two validated genetic counseling scales, participants reported favorable perceived control and satisfaction with the counseling session. Our intervention represents one model for applying traditional genetic counseling principles to risk testing for polygenetic, preventable diseases, such as type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Aconselhamento Genético , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Humanos
16.
Med Decis Making ; 32(4): 606-15, 2012 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22247420

RESUMO

BACKGROUND: Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. OBJECTIVE: The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. DESIGN: and Measurements Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high" and "low" genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. RESULTS: Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy (38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. CONCLUSIONS: While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect.


Assuntos
Tomada de Decisões , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/psicologia , Comportamentos Relacionados com a Saúde , Alfabetização em Saúde , Idoso , Técnicas de Apoio para a Decisão , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Testes Genéticos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Motivação , Sobrepeso/epidemiologia , Sobrepeso/psicologia , Medição de Risco , Fatores Socioeconômicos
17.
Clin Trials ; 8(5): 609-15, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22013171

RESUMO

BACKGROUND: The efficacy of diabetes genetic risk testing to motivate behavior change for diabetes prevention is currently unknown. PURPOSE: This paper presents key issues in the design and implementation of one of the first randomized trials (The Genetic Counseling/Lifestyle Change (GC/LC) Study for Diabetes Prevention) to test whether knowledge of diabetes genetic risk can motivate patients to adopt healthier behaviors. METHODS: Because individuals may react differently to receiving 'higher' vs 'lower' genetic risk results, we designed a 3-arm parallel group study to separately test the hypotheses that: (1) patients receiving 'higher' diabetes genetic risk results will increase healthy behaviors compared to untested controls, and (2) patients receiving 'lower' diabetes genetic risk results will decrease healthy behaviors compared to untested controls. In this paper we describe several challenges to implementing this study, including: (1) the application of a novel diabetes risk score derived from genetic epidemiology studies to a clinical population, (2) the use of the principle of Mendelian randomization to efficiently exclude 'average' diabetes genetic risk patients from the intervention, and (3) the development of a diabetes genetic risk counseling intervention that maintained the ethical need to motivate behavior change in both 'higher' and 'lower' diabetes genetic risk result recipients. RESULTS: Diabetes genetic risk scores were developed by aggregating the results of 36 diabetes-associated single nucleotide polymorphisms. Relative risk for type 2 diabetes was calculated using Framingham Offspring Study outcomes, grouped by quartiles into 'higher', 'average' (middle two quartiles) and 'lower' genetic risk. From these relative risks, revised absolute risks were estimated using the overall absolute risk for the study group. For study efficiency, we excluded all patients receiving 'average' diabetes risk results from the subsequent intervention. This post-randomization allocation strategy was justified because genotype represents a random allocation of parental alleles ('Mendelian randomization'). Finally, because it would be unethical to discourage participants to participate in diabetes prevention behaviors, we designed our two diabetes genetic risk counseling interventions (for 'higher' and 'lower' result recipients) so that both groups would be motivated despite receiving opposing results. LIMITATIONS: For this initial assessment of the clinical implementation of genetic risk testing we assessed intermediate outcomes of attendance at a 12-week diabetes prevention course and changes in self-reported motivation. If effective, longer term studies with larger sample sizes will be needed to assess whether knowledge of diabetes genetic risk can help patients prevent diabetes. CONCLUSIONS: We designed a randomized clinical trial designed to explore the motivational impact of disclosing both higher than average and lower than average genetic risk for type 2 diabetes. This design allowed exploration of both increased risk and false reassurance, and has implications for future studies in translational genomics.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Comportamentos Relacionados com a Saúde , Motivação , Projetos de Pesquisa , Aconselhamento Diretivo , Feminino , Aconselhamento Genético , Testes Genéticos , Pesquisas sobre Serviços de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde/métodos , Humanos , Entrevista Psicológica/métodos , Estilo de Vida , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Tamanho da Amostra , Marketing Social
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