Mutation update for the SATB2 gene

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120=42.5%) followed by missense variants (31/120=25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge on animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS

De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Genetics of disease, diagnosis and treatmen

Speech-language profiles in the context of cognitive and adaptive functioning in SATB2-associated syndrome

SATB2-associated syndrome (SAS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the SATB2 gene, and is typically characterized by intellectual disability and severely impaired communication skills. The goal of this study was to contribute to the understanding of speech and language impairments in SAS, in the context of general developmental skills and cognitive and adaptive functioning. We performed detailed oral motor, speech and language profiling in combination with neuropsychological assessments in 23 individuals with a molecularly confirmed SAS diagnosis: 11 primarily verbal individuals and 12 primarily nonverbal individuals, independent of their ages. All individuals had severe receptive language delays. For all verbal individuals, we were able to define underlying speech conditions. While childhood apraxia of speech was most prevalent, oral motor problems appeared frequent as well and were more present in the nonverbal group than in the verbal group. For seven individuals, age-appropriate Wechsler indices could be derived, showing that the level of intellectual functioning of these individuals varied from moderate-mild ID to mild ID-borderline intellectual functioning. Assessments of adaptive functioning with the Vineland Screener showed relatively high scores on the domain "daily functioning" and relatively low scores on the domain "communication" in most individuals. Altogether, this study provides a detailed delineation of oral motor, speech and language skills and neuropsychological functioning in individuals with SAS, and can provide families and caregivers with information to guide diagnosis, management and treatment approaches

Line of Care of the Elderly in Support of Network Fortaleza-Ce: Vision of Managers.

IntroduÃÃo Consequente ao envelhecimento populacional, as mudanÃas no perfil sociodemogrÃfico e epidemiolÃgico constituem problema de saÃde pÃblica, ensejando a necessidade de criaÃÃo de polÃticas e prÃticas de saÃde voltadas para esta populaÃÃo. Fortaleza à uma cidade com dois milhÃes e meio de habitantes, com um percentual de 7,48% de idosos. Avaliar como a linha de cuidado do idoso ocorre nas redes assistenciais de saÃde de Fortaleza produz informaÃÃes que podem subsidiar a tomada de decisÃo por parte da gestÃo municipal. Objetivo Compreender como a linha de cuidado do idoso acontece nas cinco redes assistenciais de saÃde de Fortaleza, na percepÃÃo de gestores atuantes neste cenÃrio. Metodologia Estudo qualitativo, com abordagem descritiva, tÃcnica de grupos focais e, para organizaÃÃo dos achados, foi empregado o Discurso do Sujeito Coletivo (LEFÃVRE, LEFÃVRE, 2006). Resultados Na Rede Assistencial EstratÃgia SaÃde da FamÃlia, destacam-se as aÃÃes de promoÃÃo da saÃde e a introduÃÃo da caderneta do idoso como instrumento de trabalho. Na Rede Assistencial Especializada, foi constatada significativa demanda reprimida em razÃo da carÃncia de serviÃos especializados no cuidado com o idoso. Na Rede Assistencial Hospitalar, nÃo se observa um cuidado especÃfico para o idoso, uma vez que ele à visto como usuÃrio comum. Na Rede Assistencial de UrgÃncia e EmergÃncia, inclui-se como prioridade a remoÃÃo e, no hospital, o atendimento conforme a gravidade. Na Rede Assistencial SaÃde Mental, uma abordagem psicossocial com envolvimento da comunidade e articulaÃÃo intersetorial. ConsideraÃÃes finais Entre os principais achados deste estudo, tem-se que a linha de cuidado do idoso na cidade de Fortaleza ainda à frÃgil, onde alguns fios se desalinham, ou se rompem, comprometendo a continuidade do cuidado. Ante o estado de transiÃÃo demogrÃfica e o perfil demogrÃfico e epidemiolÃgico atual, observa-se a necessidade de melhor integraÃÃo das redes assistenciais, ancoradas na Rede Assistencial da EstratÃgia SaÃde da FamÃlia, bem como a estruturaÃÃo de novos serviÃos especializados, objetivando melhorar a assistÃncia da populaÃÃo idosa de Fortaleza.Introduction As a result to the population aging, changes in demographic and epidemiological profile is public health problem, entailing the need to develop health policies and practices for the population. Fortaleza is a city of two and a half million inhabitants, of which 7.48% are elderly. The assessment of how the care for the elderly occurs in health assistance networks in Fortaleza produces information that can support the decision taken by the municipal government. Purpose Understanding how the way of caring for the elderly takes place in five health care networks in Fortaleza, in the perception of managers acting in this scenario. Methodology A qualitative study with descriptive approach and focus group technique. The Discourse of the Collective Subject was used to organize the findings (LEFÃVRE, LEFÃVRE, 2006). Results In the Family Health assistance network (so called EstratÃgia SaÃde da FamÃlia), the actions of health promotion and introduction of the recording book of the elderly as a working tool are highlighted. A significant unmet demand was observed due to the lack of specialized services in caring for the elderly in the Specialized assistance network. Specific care for the elderly was not observed in the Hospital assistance network, as he is seen as common user. In the Emergency assistance network, the removal is included as a priority, and in the hospital, the service applied is according to severity. In Mental Health assistance network, there is a psychosocial approach to community involvement and intersectorial coordination. Final considerations Among the main findings of this study is that the way of care for the elderly in the city of Fortaleza is still weak, where some strands are misaligned, or broken, compromising the continuity of service. Given the state of demographic transition and the demographic and epidemiological profile, there is a need for better integration of health care, anchored in the Family Health Strategy as well as the structuring of new specialized services, aiming to improve care for the elderly population of Fortaleza

Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment

CONTEXT: Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. OBJECTIVE: To assess the incidence of prostate cancer in trans women using hormone treatment. The incidence of prostate cancer in trans women using hormone treatment. DESIGN: In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. SETTING: Gender identity clinic. PARTICIPANTS: Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. RESULTS: The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). CONCLUSIONS: Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer

De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease gene

In vitro induction of trained immunity in adherent human monocytes

A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016)