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Spinal muscular atrophy linked to chromosome 5 (SMA-5q) is an autosomal recessive genetic disease caused by mutations in the SMN1 . SMA-5q is characterized by progressive degeneration of the spinal cord and bulbar motor neurons, causing severe motor and respiratory impairment with reduced survival, especially in its more severe clinical forms. In recent years, highly effective disease-modifying therapies have emerged, either acting by regulating the splicing of exon 7 of the SMN2 gene or adding a copy of the SMN1 gene through gene therapy, providing a drastic change in the natural history of the disease. In this way, developing therapeutic guides and expert consensus becomes essential to direct the use of these therapies in clinical practice. This consensus, prepared by Brazilian experts, aimed to review the main available disease-modifying therapies, critically analyze the results of clinical studies, and provide recommendations for their use in clinical practice for patients with SMA-5q. This consensus also addresses aspects related to diagnosis, genetic counseling, and follow-up of patients under drug treatment. Thus, this consensus provides valuable information regarding the current management of SMA-5q, helping therapeutic decisions in clinical practice and promoting additional gains in outcomes., Competing Interests: EZ, APQCA, JGG, MCF, JAMS: Consultant advisory, talks, and principal investigator for Biogen, Novartis, and Roche. MMB, CPDDF, MCMC, WM, CM, RHM, FN, ASBO, ALSP, PS, HV: Consultant advisory and or talks., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Objective:  The present study evaluated the profile of germline mutations present in patients who underwent genetic counseling for risk assessment for breast cancer (BC), ovarian cancer (OC), and endometrial cancer (EC) with a possible hereditary pattern., Methods:  Medical records of 382 patients who underwent genetic counseling after signing an informed consent form were analyzed. A total of 55.76% of patients (213/382) were symptomatic (personal history of cancer), and 44.24% (169/382) were asymptomatic (absence of the disease). The variables analyzed were age, sex, place of birth, personal or family history of BC, OC, EC, as well as other types of cancer associated with hereditary syndromes. The Human Genome Variation Society (HGVS) nomenclature guidelines were used to name the variants, and their biological significance was determined by comparing 11 databases., Results:  We identified 53 distinct mutations: 29 pathogenic variants, 13 variants of undetermined significance (VUS), and 11 benign. The most frequent mutations were BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T, and BRCA2 c.2T> G. Furthermore, 21 variants appear to have been described for the first time in Brazil. In addition to BRCA1/2 mutations, variants in other genes related to hereditary syndromes that predispose to gynecological cancers were found., Conclusion:  This study allowed a deeper understanding of the main mutations identified in families in the state of Minas Gerais and demonstrates the need to assess the family history of non-gynecological cancer for risk assessment of BC, OC, and EC. Moreover, it is an effort that contributes to population studies to evaluate the cancer risk mutation profile in Brazil., Competing Interests: The authors have no conflict of interests to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction: The lack of tools for quality assessment of genetic counselling is recognized in national and international studies. The correlation of quality of healthcare practice with greater satisfaction of patients and affected families is also well established. The present study describes the development and validation of the first Portuguese scale for quality assessment of genetic counselling practice. It encompasses a proposal of a new tool for the evaluation of the process by professionals., Material and Methods: The definition of an initial pool of items and their organization was based on a literature review and identification of the main genetic counselling dimensions as well as the theoretical dimensions of the Reciprocal Engagement Model. After a pre-test validation the scale was submitted to psychometric validation using a sample of 30 participants who evaluated 81 genetic counselling sessions., Results: Based on statistical and empirical criteria the best items were selected. The final 50 items- version comprises five dimensions: education, counselees' characteristics and decision-making, therapeutic relationship, effects of the process on the counselees and services organization., Discussion: Results showed consistent psychometric properties of the scale supported on theoretical and practice concepts of genetic counseling. The reduced number of participants involved in psychometric validation is a limitation of the study, which reflected the reduced number of professionals in genetic healthcare services., Conclusion: The scale proposed at this study is a novel and multidimensional instrument that aimed to contribute to the improvement of genetic counselling practice in Portugal.

Objective: To identify genetic counseling programs that do not encourage therapeutic abortion for individuals with hemoglobin disorders and/or for their relatives., Method: Systematic literature review of articles published from 2001 to 2012 that are located in the PubMed, LILACS, SciELO and SCOPUS databases using keywords in Portuguese, English and Spanish and that met the inclusion and exclusion criteria described on a standardized form., Results: A total of 409 articles were located, but only eight (1.9%) were selected for analysis., Conclusion: Although seldom mentioned in the literature, educational/preventive programs targeting hemoglobinopathies are feasible and allow the affected individuals to acquire knowledge on the consequences of this condition and their odds of transmitting it.

The genetic counseling has the purpose of guiding people through a conscientious and balanced decision making process regarding procreation, helping them to understand how the hereditary succession can contribute for the occurrence or risk of recurrence of genetic illnesses, as it is the case of the sickle cell anemia. This type of anemia is the most prevalence hereditary illness in Brazil and has clinical complications that can harm the development, the quality of life and lead to death. The present article has the objective to clarify the importance of the genetic counseling for the anemia carriers or falciform trace, aiming at to point out the main characteristics of this illness, its complications and how the diagnosis is made. The study was based on the bibliographical method, looking for studies that deal with this type of anemia and genetic counseling, relating them with guidelines and data from the Health Ministry. Based on the found data, we infer the importance of genetic counseling for the individuals who present the heterozygote form of sickle cell anemia - the falcemic trace - and highlight the need to implement precocious diagnostics programs and genetic and social/psychological orientation for those with the disease or falciform trace.

Medicalization is a highly visible and widespread social phenomenon in Western societies which is expressed differently according to gender. Pregnancy is heavily medicalized, and a surveillance network surrounds pregnant women, holding them accountable for both their own health and the production of a healthy fetus. Prenatal risk control is proposed in a context where diagnostic and therapeutic possibilities overlap. This problem is aggravated by the fact that abortion is illegal in Brazil. The current article is the result of research in a genetic counseling unit that consisted of: observation of consultations, review of patient files, and interviews with health professionals. The highly medicalized context of genetic counseling is discussed, as well as physicians' perception of their own practice. The article also discusses the potential impact on women's decisions related to risks, techniques, exams, and their consequences.

Sickle cell anemia is the most prevalent genetic disease in Brazil. Screening for sickle cell trait in blood donation centers has been recommended by the Brazilian government since 1976. This screening mechanism is one of most common forms of genetic screening for sickle cell disease in the country. This article is based on an ethnographic survey of individuals undergoing genetic counseling in a large blood donation center. The article contends that confidentiality should be a prerequisite for the broad dissemination of genetic information in public health. The ethical principle of confidentiality needs to be seen as a human right and public health issue.

Purpose: To detect MD1 premutation and full mutation carriers among cataract patients and offer familial genetic counseling., Methods: We studied the DNA of 60 selected cataract patients through polymerase chain reaction analysis. This study was performed at the "Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto" where selected patients had been examined at the Cataract Outpatient Clinic from 01/01/1982 to 30/06/1995. Selection criteria were age under 55 with no obvious precipitating factor, except diabetes mellitus type 2, with or without neuromuscular signs suggestive of myotonic dystrophy., Results: Three patients were found to have a full mutation corresponding to 5% of the group. Additional affected individuals were found among patients' relatives. No premutation was found., Conclusions: These results emphazise the importance of screening for MD1 gene carriers among cataract patients, and further genetic counselling.

Genetic counselling emerged as a specialized healthcare discipline in the 1960s, and since then, various sub-specialties have developed globally, namely and more recently, psychiatric genetic counselling. This study provides a pioneering exploration of family physicians and psychiatrists' perceptions regarding genetic counselling provision and its potentialities in the context of psychiatric illnesses in Portugal. A qualitative methodology with semi-structured interviews was used. Among the participants, five were family physicians, and six were psychiatrists. Thematic analysis revealed three themes: (1) the role of genetics in healthcare, (2) barriers to psychiatric genetic counselling implementation, and (3) perceived benefits associated with its implementation. Results show that while the importance of genetics in psychiatric disorders is acknowledged, there is low literacy about genetic counselling practice from the professional groups interviewed. Also, the availability and mainstreaming of genetic testing seem to influence how genetic counselling is perceived and utilized. There is a perceived need for training and guidelines that foster the dissemination of genetics into healthcare, specifically mental healthcare. A holistic and patient-centred approach is considered essential in managing psychiatric disorders and, by extension, in psychiatric genetic counselling, as it addresses both medical and psychosocial factors. Although psychiatrists and family physicians are keen to integrate psychiatric genetic counselling into their patients' care, it seems that certain fundamental challenges still persist in genetic healthcare provision. Future research should contribute for a more comprehensive evaluation of the readiness for psychiatric genetic counselling implementation in the country., Competing Interests: Declarations. Ethics approval: The study was approved by the Committee for Ethics and Responsible Conduct in the research of the Institute for Research and Innovation in Health (Appraisal N20/CECRI/2023). Competing interests: The authors declare no competing interests. Human and animal rights: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2025. The Author(s).)

Autism spectrum disorder (ASD) is a complex challenge, influenced by genetic and environmental factors. This review focuses on the proteins calbindin (CB), calretinin (CR) and parvalbumin (PV) in the context of ASD, exploring their clinical correlations and providing a deeper understanding of the spectrum. In addition, we seek to understand the role of these proteins in GABAergic regulation and their implication in the pathophysiology of ASD. The studies reviewed revealed a significant decrease in PV+ interneurons in the prefrontal cortex of individuals with ASD compared with typical controls. This reduction is associated with local synaptic hyperconnectivity, characterized by an increase in the number of excitatory synapses and a reduction in inhibitory synapses. A correlation was also observed between the decrease in PV+ and the severity of the behavioural symptoms of ASD. The research highlights GABAergic imbalance as a crucial component in the neuropathology of ASD, highlighting the role of calcium-binding proteins, especially PV, in regulating neuronal excitability and modulating synaptic connectivity. These findings provide valuable insights for the development of new therapeutic strategies intended to modulate neuronal activity and improve the symptoms associated with ASD., (© 2025 International Society for Developmental Neuroscience.)

Introduction: The early neonatal period is the most critical for the newborn's life. The autopsy is important to understand the cause of death, and find other diagnoses not clinically identified. However, the rate of neonatal autopsy is declining worldwide. This study aims to characterize early neonatal death and the clinical importance of the autopsy, evaluating the concordance between clinical and pathological diagnosis., Material and Methods: Retrospective study of the clinical records of all neonates admitted to a level III Neonatal Intensive Care unit in Portugal who died during the first week of life in 10 consecutive years (2008 - 2017). In order to classify the concordance found between clinical and pathological diagnoses, the modified Goldman classification was used., Results: During the first week of life, 76 newborns died. The main causes of death were complications related with prematurity and congenital malformations. The autopsy was performed in 50 newborns. Additional findings were found in 62% of the cases, and in 12% findings with important implications for genetic counseling of future pregnancies. There was concordance between the clinical and pathological findings in 38% of cases., Discussion: An autopsy was performed more frequently in newborns with greater gestational age. The number of additional diagnoses found at autopsy, including diagnoses with implications for genetic counseling, confirm the importance of performing them., Conclusion: An autopsy should be proposed to all parents after early neonatal death, given its importance in clarifying the cause of death.

This study describes the experiences with the stigma attached to Machado-Joseph disease (MJD) in São Miguel Island, the Azores (Portugal). We draw on semi-structured interviews with persons with MJD, family members, healthcare professionals, and direct care providers recruited through the local patient's association (n = 28). Qualitative thematic analysis revealed three main themes: (i) the intense stigma associated with MJD in the past; (ii) the current tendency towards increased openness; and (iii) increased availability of information about MJD and support. The findings suggest that stigmatization was more frequent and intense in the past. Still, there is currently a decrease in the intensity of perceived stigma, accompanied by an increasing awareness about MJD within the community. The local patient's association is noted for playing a pivotal role in raising awareness about MJD in the community and fostering the confidence of individuals with MJD and their families to engage socially, which may help to reduce or mitigate feelings of stigma. This raises questions about whether the diminished stigma towards MJD in São Miguel results from heightened awareness about the condition, a decrease in the social acceptability of stigma, or a gradual internalization and normalization of stigma among individuals with MJD as a coping mechanism., (© 2024. The Author(s).)

This manuscript reviewed the state of the art about the teaching and training of human resources for genetics and genomics in Brazil. We presented the national scenario of teaching genetics in medical undergraduate and other health courses. We discussed the training of medical geneticists through medical residency and addressed the training in genetics of physicians from specialties other than genetics. We examined the training of health professionals specializing in genetics through lato sensu and stricto sensu postgraduate programs and presented the proposals for multi-professional residency in genetic counseling and genetics and genomics that are currently the subject of discussion in the country. Finally, we highlighted the importance of training primary health care professionals concerning genetics and genomics for the effective establishment of a line of care for individuals with genetic disorders in the Brazilian Unified Health System. Therefore, we provided a thorough overview of how genetics is (or is not) incorporated into professional training in a comprehensive public healthcare system such as the Brazilian., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Genetic counseling plays a crucial role in providing individuals and families with comprehensive information, support, and guidance regarding genetic conditions. This article explores the benefits of the integration of the genetic counselor (GC) professional in Portugal and based on evidence collected from two focus group comprising Portuguese medical geneticists. The findings highlight the agreement of medical geneticists on the relevancy of GCs' integration into national healthcare as well as the need for education and training programs to enhance the genetics literacy of other healthcare professionals and increase public awareness and support for genetic counseling services. By incorporating GCs and adopting some actions suggested by participants as part of a future national strategy, Portugal can improve access to personalized genetic services and empower individuals to make informed decisions about their genetic health., (© 2024 National Society of Genetic Counselors.)

Genetic tests for dilated cardiomyopathy (DCM) have a diagnostic yield of up to 40%, but there is significant genetic heterogeneity and other challenges, such as variable expressivity and incomplete penetrance. Pedigree analysis is essential for distinguishing between sporadic and familial DCM cases by assessing family history. Familial DCM yields higher results in genetic testing, but sporadic DCM does not rule out the possibility of a genetic cause. Some genes have specific phenotypes, with the Lamin gene ( LMNA ) being associated with a phenotype of malignant arrhythmias and advanced heart failure (HF). The presence of a causal genetic variant can also aid in prognostic evaluation, identifying more severe cases with lower rates of reverse remodeling (RR) compared to individuals with a negative genotype. Current guidelines recommend genetic evaluation and counseling for individuals with DCM, along with cascade screening in first-degree relatives in cases where one or more variants are identified, offering an opportunity for early diagnosis and treatment. Relatives with a positive genotype and negative phenotype are candidates for serial evaluation, with frequency varying by age. Genotype also assists in individualized recommendations for implantable cardioverter-defibrillator (ICD) placement and advice regarding physical activity and family planning. Ongoing studies are progressively elucidating the details of genotype/phenotype relationships for a large number of variants, making molecular genetics increasingly integrated into clinical practice.

Objective:  The study aimed to characterize the clinical, histological, and immunohistochemical profile of women with invasive breast cancer, according to the risk for Hereditary Predisposition Breast and Ovarian Cancer Syndrome in a Brazilian population., Methods:  This is a retrospective study performed from a hospital-based cohort of 522 women, diagnosed with breast cancer treated at an oncology referral center in the Southeast region of Brazil, between 2014 and 2016., Results:  Among the 430 women diagnosed with invasive breast cancer who composed the study population, 127 (29.5%) were classified as at increased risk for hereditary predisposition to breast and ovarian cancer syndrome. There was a lower level of education in patients at increased risk (34.6%) when compared with those at usual risk (46.0%). Regarding tumor characteristics, women at increased risk had higher percentages of the disease diagnosed at an advanced stage (32.3%), and with tumors > 2cm (63.0%), with increased prevalence for both characteristics, when compared with those at usual risk. Furthermore, we found higher percentages of HG3 (43.3%) and K i -67 ≥ 25% (64.6%) in women at increased risk, with prevalence being about twice as high in this group. The presence of triple-negative tumors was observed as 25.2% in women at increased risk and 6.0% in women at usual risk, with the prevalence of absence of biomarkers being 2.5 times higher among women in the increased risk group., Conclusion:  From the clinical criteria routinely used in the diagnosis of breast cancer, the care practice of genetic counseling for patients at increased risk of hereditary breast cancer in contexts such as Brazil is still scarce., Competing Interests: The authors have no conflict of interests to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

This paper explores ways in which genetic risk foregrounds forms of responsibility while dealing with reproduction. We analyzed individual and family semi-structured interviews (n = 35) with people at-risk for or affected by transthyretin-related familial amyloid polyneuropathy (TTR-FAP) and Machado-Joseph disease (MJD), which are late-onset neurological diseases. Although generally considered as rare diseases, some areas in Portugal present the world's highest frequency for MJD and TTR-FAP. Thematic analysis of the data revealed that participants drew on various - sometimes ambivalent and competing - understandings of their genetic risk and their wish to have children. Some participants perceived the avoidance of genetic risk to be responsible behavior, while, for others, responsibility entailed accepting risks because they prioritized values such as parenthood, family relationships and the value of life, above any question of genetic disease. Some participants shared accounts that were fraught with ambivalence, repentance and guilt, especially when children were born before participants knew of their own or their partner's risk. Participants' accounts also showed they make continued efforts to see themselves as responsible persons and to appear responsible in the eyes of others. We discuss findings in the context of participants' negotiation between genetic risk and their sense of responsibility toward themselves and others; we conclude that "genetic responsibility" is present not only in accounts of those who chose not to have children but also in those who make an informed decision to have at-risk children., (© 2021 National Society of Genetic Counselors.)

Introduction: Chromosome abnormalities contribute to about 10% of cases of premature ovarian insufficiency. Most are associated with X chromosome. Fragile mental retardation 1 (FMR1) gene premutation has an estimated prevalence of 1% - 7% in sporadic cases and up to 13% in familial cases. Our aim was to describe the clinical characteristics, cytogenetic and FMR1 testing of a Portuguese population with premature ovarian insufficiency., Material and Methods: Women diagnosed with premature ovarian insufficiency in a Portuguese tertiary centre were retrospectivelyanalysed. Data were retrieved from electronic medical records including clinical characteristics, cytogenetic and FMR1 testing. The main outcome measures were the prevalence of chromosome abnormalities and FMR1 premutation in a Portuguese population with premature ovarian insufficiency., Results: Ninety-four patients were included, with a median age at menopause of 36 years. The prevalence of chromosome abnormalities was 16.5% (14/85) and most were X chromosome related (78.6%). The prevalence of FMR1 premutation was 6.7% (6/90). The prevalence of karyotypic abnormalities or FMR1 premutation did not differ significantly between familial and sporadic cases. Neither chromosome abnormalities nor FMR1 premutation influenced age at menopause or follicle stimulating hormone levels at diagnosis in premature ovarian insufficiency patients., Discussion: This is the first study describing the clinical characteristics and both cytogenetic and FMR1 testing in a Portuguese population with premature ovarian insufficiency. The rate of chromosome abnormalities in our sample was higher than in other populations, while the prevalence of FMR1 premutation was similar to previous reports., Conclusion: Our results underline the importance of genetic screening in premature ovarian insufficiency patients in both etiological study and genetic counselling.

Introduction: Sequence variants in the GJB2 gene account for up to 50% of cases of non-syndromic sensorineural hearing loss in the Caucasian population. In this study, we report the frequency of the less common variants of the GJB2 gene in a Portuguese sample and compare these frequencies with those of a group of hearing-impaired patients., Material and Methods: In order to select the less common GJB2 variants, 147 hearing-impaired patients followed in Centro Hospitalar Universitário de São João were evaluated. Afterwards, the presence of those variants was tested in 360 individuals from Generation 21., Results: The patient assessment enabled the selection of 11 GJB2 variants. Of those, 10 were investigated in Generation 21 participants, with only four being detected, in heterozygosity: p.Phe83Leu, p.Arg127His, p.Val153Ile and p.Asn206Ser, with the allelic frequencies (95% confidence interval) of 0.14% (0.01% - 0.87%), 0.28% (0.01% - 1.08%), 0.97% (0.43% - 2.04%) and 0.14% (0.01% - 0.88%), respectively. Two variants, p.Val37Ile and p.Val95Met, were more frequent in the patients' group with statistical significance., Discussion: Our results allow for the p.Arg127His and p.Val153Ile variants to comply with polymorphism criteria and support the pathogenicity of p.Val37Ile and p.Val95Met variants. Moreover, two cases of moderate hearing loss were explained by the p.Val37Ile/p. Asn206Ser genotype, substantiating both the pathogenicity of such variants and the hypothesis that compound heterozygosity with p.Ans206Ser is associated with mild-moderate genotypes., Conclusion: Understanding the role of the variants is essential in order to provide genetic counselling to patients and their families. We explored a set of uncommon GJB2 variants that comprised 12% of the hearing-impaired patients in this study, supporting the relevance of their description.

Objective: to discuss strategic challenges in complex health organizations sustained by an analysis in a Medical Genetics Center at a National Health Research Institute in Brazil., Method: Démarche Stratégique adapted for use with research institutes, including the policy formulation function. The study used institution's databases and workshops with key actors between Dec/2014 and Jun/2015., Results: Were defined the segments: clinical diagnosis, lysosomal diseases, osteogenesis imperfecta, genetic counseling, cytogenetics, biochemistry, and genomics. The findings reveal that the segments are aligned with the Institute's mission when it comes to referral care, although investment is required in strategic areas. The clinical diagnosis, lysosomal diseases, and genomics segments stood out in the scientific output portfolio. The findings show that progress needs to be made with policy implementation and planning to improve access to new technologies, together with investment in training and development, and the strengthening of coordination and collaboration between research institutes and referral services and between the wider healthcare network and research, care, and teaching. The inclusion of the policy formulation dimension was essential to highlight the unique role medical genetics plays in Brazil's public health system and the importance of developing action plans in the field of public health.

Objective: To describe the prevalence of hemoglobinopathies in the Brazilian adult population, according to laboratory tests from the National Health Survey., Methods: A descriptive study was carried out with National Health Survey laboratory data collected between 2014 and 2015. The hemoglobinopathies test was performed using the High Performance Liquid Chromatography method. The results of the individual tests were interpreted as providing normal, homozygous or heterozygous results for S, C and D hemoglobin, in addition to other possible hemoglobinopathies. Prevalence of hemoglobinopathies according to gender, skin color, region, age and schooling was estimated., Results: Hemoglobinopathies were present in 3.7% of the population. The main ones were the sickle cell trait (2.49%), thalassemia minor (0.30%) and suspected thalassemia major (0.80%). In relation to the sickle cell trait and suspected thalassemia major, there was a statistically significant difference for the skin color variable (p<0.05). The prevalences found for sickle cell trait according to skin color was: 4.1% among dark-skinned blacks, 3.6% among light-skinned blacks, 1.2% among whites, and 1.7% among others., Conclusion: The most prevalent hemoglobinopathies were the sickle cell trait and minor thalassemia, and were predominate among light- and dark-skinned black people. The study helps in identifying hemoglobinopathies and in genetic counseling in pre-conception.

Introduction: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996., Material and Methods: We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015)., Results: A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations., Discussion: The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent)., Conclusion: This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.

The clinical management and decision-making in pregnancies in which there is suspicion of lethal fetal malformations during the prenatal period, such as lethal skeletal dysplasia (SD), demand a multidisciplinary approach coordinated by an experienced physician. Based on the presentation of a case of osteogenesis imperfecta type IIA, we offer and discuss recommendations with the intention of organizing clinical and laboratory investigations aiming toward the clinical management, prognosis, and etiological diagnosis of these malformations, as well as genetic counselling to patients who wish to become pregnant., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

Maternally inherited diabetes and deafness is a rare form of diabetes caused by a mitochondrial DNA mutation. The index case is a 55-year-old woman who was admitted with hypertrophic cardiomyopathy. She had a history of diabetes mellitus and hearing loss. The patient's mother, two brothers and two sisters also had a history of diabetes and hearing loss. This pattern suggests a maternally inherited disorder. All siblings carried the A3243G mitochondrial DNA mutation. The identification of people with monogenic forms of diabetes mellitus is a diagnostic challenge. This condition should be considered whenever there is a history of diabetes associated with hearing loss and a relevant family history. Cardiopathy is also known to be an important feature of mitochondrial disease. In order to identify this aetiology, family screening, genetic counselling and screening of associated comorbidities are encouraged.

In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of Alzheimer disease and frontotemporal dementia in clinical practice, based on international consensus documents (currently containing partly outdated information) and published scientific evidence on this topic. Alzheimer disease may be caused by mutations in PSEN1, PSEN2 and APP. APOE genotyping is not recommended for the diagnostic or genetic counseling purposes in Alzheimer disease. Frontotemporal dementia may be caused by mutations in several genes such as c9orf72, PGRN, MAPT, TBK1, VCP, SQSTM1, and UBQLN2. This paper pragmatically approaches the process of genetic diagnosis in Alzheimer disease and frontotemporal dementia, with specific recommendations for both disorders.

Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most frequent inborn conditions. It is caused by distinct mutations in the CYP21A2 gene and in the majority of cases the disease's severity correlates with CYP21A2 allelic variation Our aim was to describe the mutational spectrum of CYP21A2 and evaluate genotype-phenotype correlation in a cohort of portuguese patients with 21-hydroxylase deficiency., Material and Methods: Retrospective study of 22 patients with clinical diagnosis of 21-hydroxylase deficiency. Molecular analysis of CYP21A2 was performed and genotype-phenotype correlation was then established., Results: Genotyping was performed in 22 unrelated patients: 5 with classic salt-wasting (average age of diagnosis 10,2 days; minimum 1, maximum 20 days), 7 with classic simple virilizing (average age of diagnosis 3,5 years; minimum 0 days, maximum 7 years) and 10 with nonclassical form (average age of diagnosis 5,7 years; minimum 4 years, maximum 8 years). The most frequent genetic defects in the classic forms were I2 splice (24%) and I172N (24%), followed by Q318X (16%) and gene deletions (16%) and in the nonclassical form, the V281L (80%). The overall concordance between genotype and phenotype was 81,8%. Genotype accurately predicted phenotype in 83,3%, 100% and 90% of patients with classic salt-wasting, classic simple virilizing and nonclassical mutations, respectively., Discussion: The frequency of genetic defects in our patients was comparable to similar studies. In most cases there was a good correlation between genotype and phenotype., Conclusions: Molecular analysis of CYP21A2 provides useful information in terms of prediction of disease severity, genetic and prenatal counseling.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG) 90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition., Competing Interests: Disclosure: The authors report no conflicts of interest.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome., (© 2022 Wiley Periodicals LLC.)

Mortality due to breast cancer could be reduced via screening programs where preliminary clinical tests employed in an asymptomatic well-population with the objective of identifying cancer biomarkers could allow earlier referral of women with altered results for deeper clinical analysis and treatment. The introduction of well-population screening using new and less-invasive technologies as a strategy for earlier detection of breast cancer is thus highly desirable. Herein, spectrochemical analyses harnessed to multivariate classification techniques are used as a bio-analytical tool for a Breast Cancer Screening Program using liquid biopsy in the form of blood plasma samples collected from 476 patients recruited over a 2-year period. This methodology is based on acquiring and analysing the spectrochemical fingerprint of plasma samples by attenuated total reflection Fourier-transform infrared spectroscopy; derived spectra reflect intrinsic biochemical composition, generating information on nucleic acids, carbohydrates, lipids and proteins. Excellent results in terms of sensitivity (94%) and specificity (91%) were obtained using this method in comparison with traditional mammography (88-93% and 85-94%, respectively). Additional advantages such as better disease prognosis thus allowing a more effective treatment, lower associated morbidity, fewer false-positive and false-negative results, lower-cost, and higher analytical frequency make this method attractive for translation to the clinical setting.

Gastric cancer remains one of the most lethal cancers. The incidence and mortality rates are quite similar. The main reason for the high mortality is diagnosis at advanced stages of disease, when treatment options are poor. One of the supposed strategies to overcome late-stage diagnosis is identifying people at high risk with the aim of establishing rigorous clinical control, including routine endoscopy and biopsies. Hereditary gastric cancer (HGC) syndromes, though representing a sizeable group to monitor for prevention or, at least, for early diagnosis, are apparently extremely rare. The low rate of HGC diagnosis might be related to the low rates of suspicion, insufficient familiarity about clinical diagnosis criteria, and the supposed conditional necessity of a molecular diagnosis. In this review, we will discuss simple measures to increase HGC diagnosis by applying three rules that might provide an opportunity for precision care to benefit the families affected by this disease., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest. No financial support., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Autism spectrum disorder is a complex and genetically heterogeneous disorder, which has hampered the identification of the etiological factors in each patient and, consequently, the genetic counseling for families at risk. However, in the last decades, the remarkable advances in the knowledge of genetic aspects of autism based on genetic and molecular research, as well as the development of new molecular diagnostic tools, have substantially changed this scenario. Nowadays, it is estimated that using the currently available molecular tests, a potential underlying genetic cause can be identified in nearly 25% of cases. Combined with clinical assessment, prenatal history evaluation and investigation of other physiological aspects, an etiological explanation for the disease can be found for approximately 30 to 40% of patients. Therefore, in view of the current knowledge about the genetic architecture of autism spectrum disorder, which has contributed for a more precise genetic counseling, and of the potential benefits that an etiological investigation can bring to patients and families, molecular genetic investigation has become increasingly important. Here, we discuss the current view of the genetic architecture of autism spectrum disorder, and list the main associated genetic alterations, the available molecular tests and the key aspects for the genetic counseling of these families. RESUMO O transtorno do espectro autista é um distúrbio complexo e geneticamente heterogêneo, o que sempre dificultou a identificação de sua etiologia em cada paciente em particular e, por consequência, o aconselhamento genético das famílias. Porém, nas últimas décadas, o acúmulo crescente de conhecimento oriundo das pesquisas sobre os aspectos genéticos e moleculares desta doença, assim como o desenvolvimento de novas ferramentas de diagnóstico molecular, tem mudado este cenário de forma substancial. Atualmente, estima-se que, por meio de testes moleculares, é possível detectar uma alteração genética potencialmente causal em cerca de 25% dos casos. Considerando-se também a avaliação clínica, a história pré-natal e a investigação de outros aspectos fisiológicos, pode-se atribuir uma etiologia para aproximadamente 30 a 40% dos pacientes. Assim, em vista do conhecimento atual sobre a arquitetura genética do transtorno do espectro autista, que tem tornado o aconselhamento genético cada vez mais preciso, e dos potenciais benefícios que a investigação etiológica pode trazer aos pacientes e familiares, tornam-se cada vez mais importantes os testes genéticos moleculares. Apresentamos aqui uma breve discussão sobre a visão atual da arquitetura genética dos transtornos do espectro autista, listando as principais alterações genéticas associadas, os testes moleculares disponíveis e os principais aspectos a se considerar para o aconselhamento genético destas famílias.

Williams-Beuren syndrome (WBS) is a genetic disorder characterized by physical and intellectual developmental delay, associated with congenital heart disease and facial dysmorphism. WBS is caused by a microdeletion on chromosome 7 (7q11.23), which encompasses the elastin (ELN) gene and about 27 other genes. The gold standard for WBS laboratory diagnosis is FISH (fluorescence in situ hybridization), which is very costly. As a possible alternative, we investigated the accuracy of three clinical diagnostic scoring systems in 250 patients with WBS diagnosed by FISH. We concluded that all three systems could be used for the clinical diagnosis of WBS, but they all gave a low percentage of false-positive (6.0-9.2%) and false-negative (0.8-4.0%) results. Therefore, their use should be associated with FISH testing.

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome., Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome., Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA., Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.

From 1986 to 2002, we examined the chromosomal composition of 916 patients attended by two genetic counseling services in the city of Pelotas, in the Brazilian State of Rio Grande do Sul, to determine the genetic causes of their disturbances. Patterns of G-banding using trypsin and Giemsa (GTG) and C-banding using barium and Giemsa (CBG) were studied using phytohemagglutinin M-stimulated lymphocytes cultured from peripheral blood. Among the patients, 110 had Down's syndrome, 7 had Edward's syndrome, 4 had Patau's syndrome, 29 had Turner's syndrome, 5 had Klinefelter's syndrome, and 3 had "cri-du-chat" syndrome. Abnormal chromosomes were observed in 29.3% of the patients. Most of these (56.3%) were numerical abnormalities, with the remaining being structural variants.

Trisomy 13 is a clinically severe entity; 85% of the patients do not survive beyond one year, and most children die before completing six months of age. We report a female child, 28 months old, white, the fourth child of a non-consanguineous couple, who presented trisomy 13. The child was born at term, from a vaginal delivery, weighing 2600 g. At birth, she was cyanotic, icteric, spastic, and cried weakly. The initial clinical examination detected polydactyly in the left hand, congenital clubfoot and convex soles, ocular hypertelorism, a low nasal bridge, numerous hemangiomas distributed throughout the body, cardiomegaly, and perimembranous inter-ventricular communication. There was no cleft lip or palate. On physical examination at 18 months old, the child weighed 6,900 g, had a cephalic perimeter of 41 cm, a thoracic perimeter of 43 cm and was 76 cm tall. At 28 months, she weighed 10,760 g and was 88.5 cm tall. Neuropsychomotor development retardation was evident from birth and, according to the psychologist and the social assistant of APAE (Handicapped Parents and Friends Association) in Canguçu, Rio Grande do Sul, there was a noticeable improvement after physiotherapy and recreational sessions.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder due to an inborn error of cholesterol metabolism, characterized by congenital malformations, dysmorphism of multiple organs, mental retardation and delayed neuropsychomotor development resulting from cholesterol biosynthesis deficiency. A defect in 3 -hydroxysteroid-delta7-reductase (delta7-sterol-reductase), responsible for the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, causes an increase in 7-DHC and frequently reduces plasma cholesterol levels. The clinical diagnosis of SLOS cannot always be conclusive because of the remarkable variability of clinical expression of the disorder. Thus, confirmation by the measurement of plasma 7-DHC levels is needed. In the present study, we used a simple, fast, and selective method based on ultraviolet spectrophotometry to measure 7-DHC in order to diagnose SLOS. 7-DHC was extracted serially from 200 l plasma with ethanol and n-hexane and the absorbance at 234 and 282 nm was determined. The method was applied to negative control plasma samples from 23 normal individuals and from 6 cases of suspected SLOS. The method was adequate and reliable and 2 SLOS cases were diagnosed.

Children with Sotos syndrome have growth acceleration, macrocephaly, acromegaloid features and delay in neuropsychomotor development during infancy. Syndrome delineation and differential diagnosis are based on evaluation of phenotypic characteristics and evolutive history of the patients. Seven patients with this syndrome are reported, and the relative occurrence of the phenotypic characteristics present in 198 reported cases are reviewed. Motor difficulties present in those patients during early infancy are responsible for the poor performance on IQ tests. Oriented stimulation should be encouraged in order to help the affected children to overcome their initial difficulties and to achieve normal scholarity and life performance.