["Revealing in the gerund": secrecy and stigma in practices of care for children and adolescents living with HIV/Aids]. / "Revelando", no gerúndio: segredo e estigma nas práticas de cuidado às crianças e adolescentes vivendo com HIV/Aids.

This article analyzes practices of care and the HIV diagnosis disclosure process to children and adolescents living with HIV/AIDS. A case study was conducted in an outpatient clinic located in a public hospital in Rio de Janeiro through participant observation, semi-structured interviews with health professionals, and the consultation of documents produced by the professionals. The analysis, based on the sociology of Simmel and Goffman, points to the revelation of the diagnosis as a hallmark that accompanies all the care established with users and sheds light on issues such as secrecy, stigma and the possible understandings about the health condition established. As a result, institutionalized relationships contribute to a progressive contact with the condition of bearing a stigma and enable phases of a patient's life protected by information to exist.

O artigo analisa as práticas de cuidado e o processo de revelação do diagnóstico a crianças e adolescentes vivendo com HIV/Aids. Foi realizado um estudo de caso em um ambulatório localizado em um hospital público do Rio de Janeiro (RJ), através de observação participante, entrevistas semiestruturadas com profissionais de saúde e consulta a documentos produzidos pelos profissionais. A análise, baseada na sociologia de Simmel e Goffman, aponta a revelação do diagnóstico como uma marca que acompanha todo o cuidado estabelecido com os usuários e dá luz a questões como o segredo, o estigma e as possíveis compreensões acerca da condição de saúde estabelecidas. Com isso, as relações institucionalizadas contribuem para um progressivo contato com a condição de portador de um estigma e fazem existir fases de uma carreira de doente protegido pela informação.

"Revelando", no gerúndio: segredo e estigma nas práticas de cuidado às crianças e adolescentes vivendo com HIV/Aids / "Revealing in the gerund": secrecy and stigma in practices of care for children and adolescents living with HIV/Aids

Resumo O artigo analisa as práticas de cuidado e o processo de revelação do diagnóstico a crianças e adolescentes vivendo com HIV/Aids. Foi realizado um estudo de caso em um ambulatório localizado em um hospital público do Rio de Janeiro (RJ), através de observação participante, entrevistas semiestruturadas com profissionais de saúde e consulta a documentos produzidos pelos profissionais. A análise, baseada na sociologia de Simmel e Goffman, aponta a revelação do diagnóstico como uma marca que acompanha todo o cuidado estabelecido com os usuários e dá luz a questões como o segredo, o estigma e as possíveis compreensões acerca da condição de saúde estabelecidas. Com isso, as relações institucionalizadas contribuem para um progressivo contato com a condição de portador de um estigma e fazem existir fases de uma carreira de doente protegido pela informação.

Abstract This article analyzes practices of care and the HIV diagnosis disclosure process to children and adolescents living with HIV/AIDS. A case study was conducted in an outpatient clinic located in a public hospital in Rio de Janeiro through participant observation, semi-structured interviews with health professionals, and the consultation of documents produced by the professionals. The analysis, based on the sociology of Simmel and Goffman, points to the revelation of the diagnosis as a hallmark that accompanies all the care established with users and sheds light on issues such as secrecy, stigma and the possible understandings about the health condition established. As a result, institutionalized relationships contribute to a progressive contact with the condition of bearing a stigma and enable phases of a patient's life protected by information to exist.

Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.

Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

Clinical findings and structural analysis involving a patient with a novel KLHL15 variant.

A de novo novel variant of uncertain significance p. (Arg532del) in the KLHL15 gene was identified by trio exome analysis in a child with global developmental delay, coarse facial features, repetitive behaviour, increased fatigability, poor feeding and gastro-oesophageal reflux. Comparative modelling and structural analysis were performed to gain insight into the effects of the variant on KLHL15 protein structure and function, with a view to aiding variant classification. The p. (Arg532del) variant affects a highly conserved residue within one of the Kelch repeats of the KLHL15 protein. This residue contributes to the stability of loop regions at the substrate binding surface of the protein; comparative modelling of the variant protein predicts altered topology at this surface, including at residue Tyr552, which is known to be important for substrate binding. We propose that it is highly probable that the p. (Arg532del) variant has a deleterious impact on KLHL15 structure, leading to a reduced level of protein function in vivo.

Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans.

BACKGROUND: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder. METHODS: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants. RESULTS: We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures. CONCLUSION: Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-ß-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Antifungal activity and genomic characterization of the biocontrol agent Bacillus velezensis CMRP 4489.

The development of bio-based products has increased in recent years, and species of the Bacillus genus have been widely used for product development due to their elevated production of antimicrobial molecules and resistance to extreme environmental conditions through endospore formation. In this context, the antifungal potential of Bacillus velezensis CMRP 4489 was investigated using in silico predictions of secondary metabolites in its genome and in vitro tests against the following phytopathogenic fungi: Sclerotinia sclerotiorum, Macrophomina phaseolina, and Botrytis cinerea. The in-silico predictions indicated that CMRP 4489 possesses several Biosynthetic Gene Clusters (BGCs) capable of producing molecules with antifungal properties and other non-identified BGCs. The in vitro assay results evidenced strong antifungal activity, inhibiting more than 60% of the tested fungi, and the isolate's molecules were stable under diverse physicochemical conditions. The in vitro assay evidenced significant antifungal activity, deformation of the hyphal structure in SS, biofilm formation capacity, and swarming motility. In the colonization assay, we observed attachment, colonization, and net-shaped biofilm formation, with the strain transitioning from the seeds to nearby structures. Therefore, CMRP 4489 showed to be a potential biocontrol agent against various diseases with agronomic importance and can be used under adverse environmental conditions.

Cataract, abnormal electroretinogram and visual evoked potentials in a child with SMA-LED2 - extending the phenotype.

This case report describes a girl who presented antenatal arthrogryposis and postnatal hypotonia, generalized and respiratory weakness, joint deformities particularly affecting the lower limbs and poor swallow. By 5 months, cataracts, abnormal electroretinograms, visual evoked potentials (VEPs) and global developmental impairments were recognized. No causative variants were identified on targeted gene panels. After her unexpected death at 11 months, gene-agnostic trio whole exome sequencing revealed a likely pathogenic de novo BICD2 missense variant, NM_001003800.1, c.593T>C, p.(Leu198Pro), confirming the diagnosis of spinal muscular atrophy lower extremity predominant type 2 (SMA-LED2). We propose that cataract, abnormal electroretinograms and VEPs are novel features of SMA-LED2.

Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.

Traboulsi syndrome caused by mutations in ASPH: An autosomal recessive disorder with overlapping features of Marfan syndrome.

Traboulsi syndrome, otherwise known as facial dysmorphism, lens dislocation, anterior-segment abnormalities and spontaneous filtering blebs, is an autosomal recessive condition associated with characteristic ocular features including dislocated crystalline lenses, anterior segment abnormalities and in some individuals, non-traumatic conjunctival cysts. There is a distinctive facial appearance which includes flattened malar region with convex nasal ridge. Alterations in the aspartate beta-hydroxylase (ASPH) gene are known to be the cause of the condition. We report seven further individuals from six unrelated families with characteristic ocular and facial features. Five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Interestingly, inguinal hernias were commonly reported. Although some skeletal features were seen, these were not consistent. One of the patients had mild deficiency of factor VII on clotting studies. The ASPH protein hydroxylates specific asparagine- and aspartate-residues in epidermal growth factor (EGF)-domain containing proteins including coagulation factors and associated genes including FBN1. We propose this as an explanation for the overlap in clinical features with Marfan syndrome and conclude that Traboulsi syndrome is an important differential diagnosis. We strongly recommend echocardiography surveillance for patients with Traboulsi syndrome.

Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms.

Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene <i>DNM1L</i>, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.

Rapid exome sequencing in critically ill children impacts acute and long-term management of patients and their families: A retrospective regional evaluation.

INTRODUCTION: Genetic disorders are a significant cause of paediatric morbidity and mortality. Rapid exome sequencing was introduced by the National Health Service (NHS) in England on 1st October 2019 for acutely unwell children with a likely monogenic disorder, or to inform current pregnancy management where there was a previously affected child or fetus. We present results of a 12-month patient cohort from one large clinical genetics centre in England. METHODS: Patients were identified through local genetics laboratory records. We included all cases which underwent rapid exome sequencing between 1st October 2020 and 30th September 2021. DNA was extracted, quality checked and exported to the Exeter Genomic laboratory where library preparation, exome sequencing of all known human genes, gene-agnostic bioinformatic analysis, variant interpretation, MDT discussions and reporting were performed. RESULTS: Ninety-five probands were included. Trio analysis was performed in 90% (85), duo in 8% (8), singleton in 2% (2). The median turnaround time for preliminary reports was 11 days. The overall diagnostic yield was 40% (38 patients); 36% (34 patients) made solely on exome with a further 4% on concomitant exome and microarray analysis. Highest diagnostic rates were seen in patients with neuro-regression, skeletal dysplasia, neuromuscular and neurometabolic conditions. Where the diagnosis was made solely through exome sequencing, management was altered for the proband or family in 97% (33/34). For the proband, this was most commonly that the diagnosis was able to inform current management and prognosis (20 patients, 59%), as well as direct specialist referrals (10 patients, 29%). For families, the exome sequencing results provided accurate recurrence risk counselling in 88% (30/34) with cascade testing offered if indicated in some families. CONCLUSIONS: In the majority of cases, the genetic diagnoses influenced acute and long-term management for critically ill children and their families. Paediatric and neonatal clinicians in the NHS now have direct access to exome sequencing for their patients. The rapid turnaround time was particularly helpful to alter the management in acute clinical settings and is a powerful tool for diagnosing monogenic conditions. This study is an example of a highly successful integration of a national rapid exome sequencing service with diagnostic rates comparable to previously reported literature.

UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.

Dysmorphism and immunodeficiency - One of the differential diagnoses is PAX1 related otofaciocervical syndrome type 2.

Otofaciocervical syndrome (OTFCS) is a rare condition associated with short stature, abnormal facial features and conductive hearing loss. OTFCS type 2 (OTFCS) is an autosomal recessive form of this condition with associated T cell deficiency due to biallelic variants in PAX1. We report a female child born to a consanguineous couple with homozygous PAX1 variant. She was diagnosed with T cell immunodeficiency as a neonate and underwent haematopoietic stem cell transplant with cord blood at the age of 5 months. She had facial dysmorphism including ear abnormalities and spinal deformity. We present longitudinal follow-up of the proband who has responded well to the bone marrow transplant to add to the otherwise limited description of this rare condition. This case report expands on the limited literature available on this condition, with only five families reported to date and it further highlights the clinical utility of a rapid gene-agnostic trio exome analysis in identifying a genetic diagnosis in patients who previously underwent genomic testing by gene panel analysis.

Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation.

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Relationship between levels of mindfulness and substance use pattern / Relação entre níveis de mindfulness e padrão do uso de substâncias

OBJECTIVE: Evaluate the association between levels of mindfulness and sociodemographic characteristics and pattern of drug use of individuals seeking treatment in a University Service Specialized in Substance Use Disorders. METHODS: This is a cross-sectional study with 164 individuals over 18 years of age seeking treatment for the use of psychoactive substances in the June 2018-December 2019 period, using a questionnaire for sociodemographic data, the Mindful Attention Awareness Scale (MAAS) self- -reporting instrument, and the Alcohol, Smoking, and Substance Involvement Screening Test. RESULTS: An association was found between low levels of mindfulness mainly with the individual risk of being a medium/high-risk user of sedative-hypnotic drugs (p = 0.020). A borderline association was also found between MAAS and the risk of the individual being a medium/high risk of alcohol (p = 0.053) and with a more severe pattern of substance use (p = 0.065). CONCLUSION: Individuals seeking treatment for substance use presented impairments in the attentional aspect of mindfulness and levels of mindfulness seem to protect against behaviors related to substance use, especially against the use of high/ moderate risk of sedative-hypnotics.

OBJETIVO: Avaliar a associação entre níveis de mindfulness e características sociodemográficas e padrão do uso de drogas de indivíduos que buscam tratamento em Serviço Universitário Especializado em Transtorno por Uso de Substâncias. MÉTODOS: Estudo de corte transversal de 164 indivíduos acima de 18 anos que buscavam tratamento para uso de substâncias psicoativas no período de junho de 2018 a dezembro de 2019, utilizando questionário para dados sociodemográficos, o instrumento de autorrelato Mindful Attention Awareness Scale (MAAS) e o Alcohol, Smoking and Substance Involvement Screening Test. RESULTADOS: Foi encontrada associação entre baixos níveis de mindfulness principalmente com o risco de o indivíduo ser usuário de médio/alto risco de sedativos-hipnóticos (p = 0,020). Também foi encontrada associação limítrofe entre MAAS com risco de o indivíduo ser usuário de médio/alto risco de álcool (p = 0,053) e com padrão mais grave de uso de substâncias (p = 0,065). CONCLUSÃO: Indivíduos que buscavam tratamento para uso de substâncias apresentaram prejuízos no aspecto atencional de mindfulness, e níveis de mindfulness parecem proteger contra comportamentos relacionados ao uso de substâncias, principalmente contra o uso de alto/moderado risco de sedativos-hipnóticos.

THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.

Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.