Ana Alexandra Caldas Osório

Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer

It has been demonstrated that monoallelic PALB2 (Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline PALB2 mutations presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline PALB2 mutations in a set of 131 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of PALB2 gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several PALB2 variants, but no other obvious deleterious PALB2 mutation has been found. Thus, our study does not support an enrichment of PALB2 germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the PALB2 gene.

How executive functions are related to intelligence in Williams syndrome

Williams syndrome is characterized by impairments in executive functions (EFs). However, it remains unknown how distinct types of EFs relate to intelligence in this syndrome. The present study analyzed performance on working memory, inhibiting and shifting, and its links to IQ in a sample of 17 individuals with WS, and compared them with a group of 17 typically developing individuals matched on chronological age and gender. In conclusion, our results suggest that working memory, inhibiting, and shifting relate differently to intelligence in WS as well as in typical development, with working memory being the EF most closely related to intelligence in both groups. Notably, the magnitude of the associations between the three EFs and IQ was substantially higher in the WS group than in the TD group, bringing further confirmation to the notion that frontal lobe impairments may produce a general compromise of several EFs.

Emotion Understanding in Preschool Children: The Role of Executive Functions.

This investigation was aimed at studying the relations between executive functions (EFs) and categorical emotion understanding while controlling for preschoolers’ IQ, language ability and theory of mind (ToM). Specifically, we wanted to analyse the association between emotion understanding and set shifting, due to the lack of studies with this EF. Data of 75 children aged 4½ years (52% boys) was collected in two laboratory visits. Emotion understanding was assessed using the Emotion Recognition Questionnaire, inhibitory control using the Head-Toes-Knees-Shoulders task and set shifting using a version of the Dimensional Change Card Sort task. IQ was evaluated using the WPPSI-R, language using the Peabody Picture Vocabulary Test – Revised; and ToM using six standardized tasks. Set shifting, but not inhibitory control, predicted emotion understanding, over and above mothers’ age, and children’s IQ, language ability, and ToM. Mothers’ age and children’s language ability were also significant predictors in the final regression model. Results suggest that the capacity to shift mental sets is linked with inter-individual differences in children’s understanding of situational causes of emotion. Therefore studying EFs as correlates of emotion understanding is an important focus of future research.

Cognitive functioning in children and adults with Smith-Magenis syndrome.

Smith-Magenis Syndrome (SMS) is a genetic neurodevelopmental disorder caused by a microdeletion on chromosome 17p11.2. This syndrome is characterized by a distinctive profile of physical, medical and neuropsychological characteristics. The latter include general mental disability, with the majority of individuals falling within the mild to moderate range. This study reports a detailed cognitive assessment of children and adults with SMS with the use of the Wechsler intelligence scales at three distinct levels of analysis: full scale IQ, factorial indices, and subtests. Child and adult samples were each compared to samples of age and gender-matched typically developing individuals. To our knowledge, this is the first study to systematically analyse the cognitive profile of individuals with SMS in Southern Europe. The present study confirmed mental disability, particularly within the moderate category, as a consistent feature of children and adults with SMS. Furthermore, both child and adult samples evidenced significant impairments in all four indices when compared with their typically developing counterparts. A specific pattern of strengths and weaknesses was discernible for both samples, with Verbal Comprehension emerging as a relative strength, whereas Working Memory appeared as a relative weakness. Finally, with the exception of two subtests in the perceptual domain, we found no evidence for a general cognitive decline with age.

DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

Background:Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours.Methods:High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features.Results:Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours.Conclusion:Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors.

Promoting social plasticity in developmental disorders with non-invasive brain stimulation techniques

Being socially connected directly impacts our basic needs and survival. People with deficits in social cognition might exhibit abnormal behaviors and face many challenges in our highly social-dependent world. These challenges and limitations are associated with a substantial economical and subjective impact. As many conditions where social cognition is affected are highly prevalent, more treatments have to be developed. Based on recent research, we review studies where non-invasive neuromodulatory techniques have been used to promote Social Plasticity in developmental disorders. We focused on three populations where non-invasive brain stimulation seems to be a promising approach in inducing social plasticity: Schizophrenia, Autism Spectrum Disorder (ASD) and Williams Syndrome (WS). There are still very few studies directly evaluating the effects of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) in the social cognition of these populations. However, when considering the promising preliminary evidences presented in this review and the limited amount of clinical interventions available for treating social cognition deficits in these populations today, it is clear that the social neuroscientist arsenal may profit from non-invasive brain stimulation techniques for rehabilitation and promotion of social plasticity.

Microcefalia e outras manifestações relacionadas ao vírus Zika: impacto nas crianças, nas famílias e nas equipes de saúde

The present study aimed to present an overview of recent national and international research on the Zika virus (ZIKV), as well as to explore possible action plans focused on children, their families and the health teams involved.Therefore, the study proposes the implementation of tracking systems in order to identify, describe and characterize the potential correlates of prenatal exposure to ZIKV, divided into three lines of action: 1. Diagnostic and etiological evaluation as well as screening of developmental problems in children confirmed or suspected of prenatal ZIKV infection. 2. Investigation of the emotional impact, quality of life, coping strategies and support network of the affected children and their families. 3. Training of multidisciplinary teams to conduct assessments and intervention programs throughout these childrens development, especially in the first three years of life. In conclusion, the recent ZIKV outbreak in Brazil and several other Latin American countries places a significant burden on the health care systems: to understand the real meaning of a potential new teratogen; to unravel the pathogenic mechanisms of ZIKV, particularly in a prevention perspective; and to recognize the broad spectrum of clinical manifestations in order to devise intervention programs.O presente estudo objetivou apresentar um panorama nacional e internacional atual dos estudos sobre o virus Zika (ZIKV) e, ancorado no avanco deste conhecimento, refletir sobre planos de acao voltados para as criancas, familias e equipes de saude envolvidas. Neste sentido, o estudo propos a implementacao de sistemas de seguimento para conhecer, descrever e caracterizar aspectos que devem estar relacionados a exposicao pre-natal ao ZIKV, divididos em tres eixos de atuacao: 1. Avaliacao diagnostica e etiologica e rastreamento de problemas de desenvolvimento nas criancas incluidas como casos confirmados ou suspeitos. 2. Investigacao do impacto emocional, da qualidade de vida, das estrategias de enfrentamento e da rede de apoio as familias das criancas incluidas. 3. Capacitacao de equipes multiprofissionais para avaliar e elaborar programas de intervencao ao longo do desenvolvimento das criancas, principalmente nos tres primeiros anos de vida. Como conclusao, o presente trabalho ressalta que o sistema de assistencia a saude encontra-se diante de grandes desafios: entender o real significado de um potencial novo teratogeno; desvendar os mecanismos patogenicos do ZIKV, principalmente para o enfrentamento preventivo, e reconhecer o amplo espectro de manifestacoes clinicas para a elaboracao de programas de intervencao.

Autism spectrum symptoms in Smith–Magenis syndrome and Williams syndrome: comparisons and contrasts

Abstract Objectives: Genetic syndromes with distinctive cognitive and behavioural phenotypes — such as Smith–Magenis syndrome (SMS) and Williams syndrome (WS) — offer unique opportunities to explore the links between specific genes and neurodevelopmental disorders. While some studies have reported the occurrence of autistic symptoms in SMS, evidence for such symptomatology in WS is scarcer. This study is the first to compare and contrast levels of autistic symptoms in SMS and WS. Methods: Parents/caregivers of 11 individuals with SMS and 14 individuals with WS completed the Social Communication Questionnaire. Results: Results indicate that both syndromes present, albeit in distinct degrees, behavioural signs of the autistic spectrum. The SMS group scored significantly higher on both current and lifetime symptoms. The mean lifetime form score of the SMS group (particularly males) was consonant with the presence of an autism spectrum disorder. Regarding the WS group, even though the mean score was below the clinical threshold, it was still above what has been reported in typically developing samples. Conclusion: Our study contributes to a better definition of the neurobehavioural profiles of SMS and WS, as it offers comparisons and contrasts that may, in turn, prove beneficial for early diagnosis and intervention.

Psychopathology and behavior problems in children and adolescents with Williams syndrome: Distinctive relationships with cognition

ABSTRACT Several studies have documented the high prevalence of psychopathology and behavior problems in Williams syndrome (WS). However, the links between cognitive development and such symptoms need further clarification. Our study aims to expand current knowledge on levels of behavior problems and its links to cognition in a sample of Brazilian individuals with WS. A total of 25 children and adolescents with WS and their parents participated in this study. The participants’ IQs were assessed with the Wechsler Scales of Intelligence (for children or adults) and parental reports of psychopathology/behavior problems were collected using the Child Behavior Checklist (CBCL). The presence of clinically significant attention problems was a main feature in our sample of children and adolescents with WS. In the children, higher IQ scores were found to be significantly associated with less externalizing problems, while in the adolescents cognitive abilities were found to be associated with less internalizing symptoms. These results provide further insight into the links between psychopathology and behavior problems and cognitive abilities in WS, and suggest the need to take age into consideration when analyzing such relationships.

Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene

PurposeThere is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility.MethodsUsing whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer.ResultsAlthough the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited.ConclusionATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.