RESUMO
PURPOSE: To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States. METHODS: In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately. RESULTS: Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10-9, B v C P < 2.2×10-16). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%). CONCLUSION: This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.
Assuntos
Neoplasias Ovarianas , Neoplasias da Mama , Carcinoma Epitelial do Ovário , Estudos Transversais , Feminino , Células Germinativas , Hispânico ou Latino/genética , Humanos , América Latina/epidemiologia , Masculino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Prevalência , Estados Unidos/epidemiologiaRESUMO
PURPOSE: The Mexican Jewish community (MJC) is a previously uncharacterized, genetically isolated group composed of Ashkenazi and Sephardi-Mizrahi Jews who migrated in the early 1900s. We aimed to determine the heterozygote frequency of disease-causing variants in 302 genes in this population. METHODS: We conducted a cross-sectional study of the MJC involving individuals representing Ashkenazi Jews, Sephardi-Mizrahi Jews, or mixed-ancestry Jews. We offered saliva-based preconception pan-ethnic expanded carrier screening, which examined 302 genes. We analyzed heterozygote frequencies of pathogenic/likely pathogenic variants and compared them with those in the Genome Aggregation Database (gnomAD). RESULTS: We recruited 208 participants. The carrier screening results showed that 72.1% were heterozygous for at least 1 severe disease-causing variant in 1 of the genes analyzed. The most common genes with severe disease-causing variants were CFTR (16.8% of participants), MEFV (11.5%), WNT10A (6.7%), and GBA (6.7%). The allele frequencies were compared with those in the gnomAD; 85% of variant frequencies were statistically different from those found in gnomAD (P <.05). Finally, 6% of couples were at risk of having a child with a severe disorder. CONCLUSION: The heterozygote frequency of at least 1 severe disease-causing variant in the MJC was 72.1%. The use of carrier screening in the MJC and other understudied populations could help parents make more informed decisions.
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Etnicidade , Judeus , Criança , Estudos Transversais , Frequência do Gene/genética , Triagem de Portadores Genéticos/métodos , Testes Genéticos , Heterozigoto , Humanos , Judeus/genética , Pirina/genéticaRESUMO
BACKGROUND: Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes. METHODS: We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups. RESULTS: We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues). CONCLUSIONS: From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.
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Estudos de Associação Genética , Holoprosencefalia/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adulto , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Histidina/genética , Holoprosencefalia/classificação , Holoprosencefalia/etnologia , Humanos , Masculino , Tipagem Molecular , Fenótipo , Grupos Raciais , Análise de Sequência de DNARESUMO
Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association.
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Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Endofenótipos , Família/psicologia , Modelos Estatísticos , Adolescente , Adulto , Atenção , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Casos e Controles , Criança , Função Executiva , Feminino , Humanos , Inteligência , Masculino , Memória , Testes Neuropsicológicos/estatística & dados numéricos , Linhagem , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: Standard questionnaires to characterize familial attention deficit hyperactivity disorder (ADHD) of adults have been studied in some studies. AIM: To observe convergent and concurrent validity of four standard rating scales to quantify the familial ADHD symptoms of adults. PATIENTS AND METHODS: The sample was constituted by the 392 adults; aged 18 through 84 years, belonging to 141 Antioquian families with multiple ADHD affected members, who fulfilled by self-report the Wender-Utah Rating Scale and the ADHD checklist; and, beside, answered a questionnaire asking for current and past ADHD symptoms, in a neurological interview. Correlation analyses were done. Sensitivity and specificity for ADHD diagnosis were also determined. RESULTS: Significant and over 0.6 correlations were observed between scales that explored past ADHD symptoms. Distant cut-off points for 90% sensitivity and specificity were observed for all questionnaires. The best LR+ (12.15) was found for the report of 5 or more past hyperactivity-impulsivity symptoms; follow by the report of 7 or more past ADHD symptoms (6.92). CONCLUSIONS: Cut-off points should be taken with caution when these rating scales were used for adult ADHD screening. Psychometric properties do not allow using these scales as substitution of structured clinical interview for the gold standard ADHD diagnosis in adults.
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Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Escalas de Graduação Psiquiátrica/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/normas , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inquéritos e Questionários , Adulto JovemRESUMO
INTRODUCCIÓN: el sistema de evaluación de la conducta para niños (sigla del inglés: BASC) es una escala para medir la conducta y la personalidad de los niños y adolescentes.OBJETIVO: establecer el fenotipo cuantitativo del comportamiento en 30 familias nucleares de Barranquilla con un caso índice de un niño afectado con TDAH, utilizando la escala BASC. MATERIAL Y MÉTODOS: se seleccionaron 50 niños y adolescentes de ambos generos, pertenecientes a 30 familias con un caso índice de TDAH. Para el diagnóstico, se aplicó una entrevista psiquiátrica estructurada, evaluación médica y neuropsicológica. Los padres y maestros llenaron el BASC acerca de los niños y adolescentes.RESULTADOS: de acuerdo con las respuestas de los padres, el fenotipo estaría formado por síntomas de inatención en la escala clínica, con diferencias muy significativas entre los grupos y un tamaño del efecto enorme (1,45); además, informan la presencia significativamente más frecuente de síntomas atípicos en el grupo de TDAH, con un tamaño del efecto grande (0,7). En la escala de adaptación, los no afectados tienen habilidades sociales significativamente mejores, con un tamaño del efecto muy grande (1,23). En la escala clínica de maestros, los síntomas de hiperactividad muestran puntuaciones significativamente mayores en el grupo de afectados, con un tamaño del efecto muy grande (1,13); los síntomas de inatención también producen diferencias estadísticamente significativas con tamaño del efecto grande (0,98). El fenotipo cuantitativo más detectado por maestros es el de los problemas académicos, con un tamaño del efecto enorme (1,4).CONCLUSIONES: la escala multidimensional BASC permitió detectar posibles fenotipos cuantitativos del comportamiento en las familias estudiadas.