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Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, is the most common form of dementia. Currently, there is no single test that can diagnose AD, especially in understudied populations and developing countries. Instead, diagnosis is based on a combination of medical history, physical examination, cognitive testing, and brain imaging. Exosomes are extracellular nanovesicles, primarily composed of RNA, that participate in physiological processes related to AD pathogenesis such as cell proliferation, immune response, and neuronal and cardiovascular function. However, the identification and understanding of the potential role of long non-coding RNAs (lncRNAs) in AD diagnosis remain largely unexplored. Here, we clinically, cognitively, and genetically characterized a sample of 15 individuals diagnosed with AD (cases) and 15 controls from Barranquilla, Colombia. Advanced bioinformatics, analytics and Machine Learning (ML) techniques were used to identify lncRNAs differentially expressed between cases and controls. The expression of 28,909 lncRNAs was quantified. Of these, 18 were found to be differentially expressed and harbored in pivotal genes related to AD. Two lncRNAs, ENST00000608936 and ENST00000433747, show promise as diagnostic markers for AD, with ML models achieving > 95% sensitivity, specificity, and accuracy in both the training and testing datasets. These findings suggest that the expression profiles of lncRNAs could significantly contribute to advancing personalized AD diagnosis in this community, offering promising avenues for early detection and follow-up.
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Doença de Alzheimer , RNA Longo não Codificante , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Humanos , RNA Longo não Codificante/genética , Feminino , Masculino , Idoso , Medicina de Precisão/métodos , Biomarcadores , Aprendizado de Máquina , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Perfilação da Expressão Gênica/métodos , Biologia Computacional/métodosRESUMO
Background: People with Huntington's disease (HD) exhibit neurocognitive alterations throughout the disease, including deficits in social cognitive processes such as Theory of Mind (ToM). Objective: The aim is to identify methodologies and ToM instruments employed in HD, alongside relevant findings, within the scientific literature of the past two decades. Methods: We conducted a comprehensive search for relevant papers in the SCOPUS, PubMed, APA-PsyArticles, Web of Science, Redalyc, and SciELO databases. In the selection process, we specifically focused on studies that included individuals with a confirmed genetic status of HD and investigated ToM functioning in patients with and without motor symptoms. The systematic review followed the PRISMA protocol. Results: A total of 27 papers were selected for this systematic review, covering the period from 2003 to 2023. The findings consistently indicate that ToM is globally affected in patients with manifest motor symptoms. In individuals without motor symptoms, impairments are focused on the affective dimensions of ToM. Conclusions: Based on our analysis, affective ToM could be considered a potential biomarker for HD. Therefore, it is recommended that ToM assessment be included as part of neuropsychological evaluation protocols in clinical settings. Suchinclusion could aid in the identification of early stages of the disease and provide new opportunities for treatment, particularly with emerging drugs like antisense oligomers. The Prospero registration number for this review is CRD42020209769.
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Doença de Huntington , Teoria da Mente , Doença de Huntington/genética , Doença de Huntington/psicologia , HumanosRESUMO
The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.
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Síndrome do Cromossomo X Frágil , Masculino , Humanos , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/genética , Efeito Fundador , Epidemiologia Molecular , Proteína do X Frágil da Deficiência Intelectual/genética , Expansão das Repetições de Trinucleotídeos , MutaçãoRESUMO
Copy number variants (CNVs) remain a major etiological cause of neurodevelopmental delay and congenital malformations. Chromosomal microarray analysis (CMA) represents the gold standard for CNVs molecular characterization. We applied CMA throughout the patient's clinical diagnostic workup, as the patient's medical provider requested. We collected CMA results of 3380 patients enrolled for 5 years (2016-2021). We found 830 CNVs in 719 patients with potential clinical significance, that is, (i) pathogenic, (ii) likely pathogenic, and (iii) variants of uncertain significance (VUS), from which 10.6% (predominantly involving chromosomes 15 and 22) were most likely the final cause underpinning the patients' clinical phenotype. For those associated with neurodevelopmental phenotypes, the rate of pathogenic or likely pathogenic findings among the patients with CNVs was 60.75%. When considering epileptic phenotypes, it was 59%. Interestingly, our protocol identified two gains harbored in 17q21.31 and 9q34.3, internationally classified initially as VUS. However, because of their high frequency, we propose that these two VUS be reclassified as likely benign in this widely heterogeneous phenotypic population. These results support the diagnostic yield efficiency of CMA in characterizing CNVs to define the final molecular cause of genetic diseases in this cohort of Colombian patients, the most significant sample of patients from a Latino population, and define new benign polymorphic CNVs.
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Aberrações Cromossômicas , Cromossomos , Humanos , Análise em Microsséries , Cromossomos Humanos Par 15 , Variações do Número de Cópias de DNA/genéticaRESUMO
OBJECTIVE: We aim to determine the prevalence of mental disorders in siblings of children with attention deficit hyperactivity disorder (ADHD), and to determine how psychosocial adversity factors relate to this psychopathology, in a low-middle income country (Colombia). METHODS: We evaluated subjects with ADHD diagnosed according to the DSM-5 criteria, one of their parents and one of their siblings (ages 8-19). We used the ADHD rating scale and a set of instruments to assess the presence of mental disorders as well as psychosocial adversity. RESULTS: We evaluated 74 trios formed by the index case with ADHD, one sibling and one of the parents. We found that 24.3% of the participating siblings also met the criteria for ADHD and another 24.3% for other psychiatric disorders. The risk of these siblings having ADHD increased further when one of the parents reported a history of ADHD. We also found that 28.3% of the families faced high levels of psychosocial adversity as per their scores in the Rutter Adversity Index. CONCLUSIONS: Siblings of subjects with ADHD showed a significant risk for ADHD and other mental disorders. That risk increased if a parent reported a history of ADHD and also when two or more psychosocial adversity factors were present. This study supports the importance of early detection in efforts to decrease the risk for other siblings.
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Transtorno do Deficit de Atenção com Hiperatividade , Criança , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Irmãos , Estudos Transversais , Colômbia/epidemiologiaRESUMO
Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.
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Doença de Huntington , Adulto , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/diagnóstico , Colômbia , Alelos , DNA , Linhagem , Proteína Huntingtina/genética , Expansão das Repetições de TrinucleotídeosRESUMO
Objective: We aim to determine the prevalence of mental disorders in siblings of children with attention deficit hyperactivity disorder (ADHD), and to determine how psychosocial adversity factors relate to this psychopathology, in a low-middle income country (Colombia). Methods: We evaluated subjects with ADHD diagnosed according to the DSM-5 criteria, one of their parents and one of their siblings (ages 8-19). We used the ADHD rating scale and a set of instruments to assess the presence of mental disorders as well as psychosocial adversity. Results: We evaluated 74 trios formed by the index case with ADHD, one sibling and one of the parents. We found that 24.3% of the participating siblings also met the criteria for ADHD and another 24.3% for other psychiatric disorders. The risk of these siblings having ADHD increased further when one of the parents reported a history of ADHD. We also found that 28.3% of the families faced high levels of psychosocial adversity as per their scores in the Rutter Adversity Index. Conclusions: Siblings of subjects with ADHD showed a significant risk for ADHD and other mental disorders. That risk increased if a parent reported a history of ADHD and also when two or more psychosocial adversity factors were present. This study supports the importance of early detection in efforts to decrease the risk for other siblings.
Objetivo: Nuestro objetivo es determinar la prevalencia de trastornos mentales en hermanos de casos con TDAH y cómo los factores de adversidad psicosocial se relacionan con esta psicopatología en un país de ingresos bajos-medios (Colombia). Métodos: Se evaluó a sujetos con TDAH diagnosticado según los criterios del DSM-5, uno de sus padres y uno de sus hermanos (edades, 8-19 anos). Mediante la escala de calificación del TDAH y un conjunto de otros instrumentos se evaluó la presencia de trastornos mentales y adversidad psicosocial. Resultados: Se evaluó a 74 tríos formados por el caso índice con TDAH, un hermano y uno de los padres. Se halló que un 24,3% de los hermanos participantes también cumplían los criterios de TDAH y otro 24,3%, otros trastornos psiquiátricos. El riesgo de que estos hermanos tuvieran TDAH aumentó aún más cuando uno de los padres informó antecedentes de TDAH. También, que el 28,3% de las familias se enfrentaron a altos niveles de adversidad psicosocial según sus puntuaciones en el Índice de Adversidad de Rutter. Conclusiones: Los hermanos de sujetos con TDAH mostraron un significativo riesgo de TDAH y otros trastornos mentales. Ese riesgo aumenta si uno de los padres reporta antecedentes de TDAH y también cuando se presentan 2 o más factores de adversidad psicosocial. Este estudio respalda la importancia de la detección temprana con el fin de disminuir el riesgo para otros hermanos.
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INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) has genetic and environmental aetiological factors. There are few publications on the environmental factors. The objective of this review is to present the role of psychosocial adversity in the aetiology and course of ADHD. METHODS: A search was carried out in the following databases: PubMed, ScienceDirect, SciELO, ClinicalKey, EMBASE, Lilacs, OVID, APA and PsycNET. English and Spanish were selected without being limited by type of study or year of publication. Finally, a qualitative synthesis was conducted. RESULTS: ADHD development could be related to exposure to adverse factors in the family, school or social environment. It has been proposed as an explanatory mechanism that adversity interacts with genetic variants and leads to neurobiological changes. There may also be a gene-environment correlation whereby individual hereditary characteristics increase the risk of exposure to adversity, and indirectly increase the probability of developing ADHD. Research on psychosocial adversity represents a big challenge, not only due to the complexity of its construct, but also to the effect of subjective perception of a given event. CONCLUSIONS: ADHD aetiology is complex and involves the interaction of both genetic and environmental factors, in which these factors correlate and cause the disorder. The study of the role of psychosocial adversity in ADHD is fundamental, but it remains a task that entails great difficulties.
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Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Meio SocialRESUMO
BACKGROUND: Bipolar Disorder (BD) represents the seventh major cause of disability life-years-adjusted. Lithium remains as a first-line treatment, but clinical improvement occurs only in 30 % of treated patients. Studies suggest that genetics plays a major role in shaping the individual response of BD patients to lithium. METHODS: We used machine-learning techniques (Advance Recursive Partitioned Analysis, ARPA) to build a personalized prediction framework of BD lithium response using biological, clinical, and demographical data. Using the Alda scale, we classified 172 BD I-II patients as responders or non-responders to lithium treatment. ARPA methods were used to build individual prediction frameworks and to define variable importance. Two predictive models were evaluated: 1) demographic and clinical data, and 2) demographic, clinical and ancestry data. Model performance was assessed using Receiver Operating Characteristic (ROC) curves. RESULTS: The predictive model including ancestry yield the best performance (sensibility = 84.6 %, specificity = 93.8 % and AUC = 89.2 %) compared to the model without ancestry (sensibility = 50 %, Specificity = 94.5 %, and AUC = 72.2 %). This ancestry component best predicted lithium individual response. Clinical variables such as disease duration, the number of depressive episodes, the total number of affective episodes, and the number of manic episodes were also important predictors. CONCLUSION: Ancestry component is a major predictor and significantly improves the definition of individual Lithium response in BD patients. We provide classification trees with potential bench application in the clinical setting. While this prediction framework might be applied in specific populations, the used methodology might be of general use in precision and translational medicine.
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Transtorno Bipolar , Humanos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Lítio/uso terapêutico , Compostos de Lítio/uso terapêutico , Mania/tratamento farmacológicoRESUMO
Introduction: Attention deficit/hyperactivity disorder (ADHD) has genetic and environmental aetiological factors. There are few publications on the environmental factors. The objective of this review is to present the role of psychosocial adversity in the aetiology and course of ADHD. Methods: A search was carried out in the following databases: PubMed, ScienceDirect, SciELO, ClinicalKey, EMBASE, Lilacs, OVID, APA and PsycNET. English and Spanish were selected without being limited by type of study or year of publication. Finally, a qualitative synthesis was conducted. Results: ADHD development could be related to exposure to adverse factors in the family, school or social environment. It has been proposed as an explanatory mechanism that adversity interacts with genetic variants and leads to neurobiological changes. There may also be a gene-environment correlation whereby individual hereditary characteristics increase the risk of exposure to adversity, and indirectly increase the probability of developing ADHD. Research on psychosocial adversity represents a big challenge, not only due to the complexity of its construct, but also to the effect of subjective perception of a given event. Conclusions: ADHD aetiology is complex and involves the interaction of both genetic and environmental factors, in which these factors correlate and cause the disorder. The study of the role of psychosocial adversity in ADHD is fundamental, but it remains a task that entails great difficulties.
Introducción: El trastorno por déficit de atención con hiperactividad (TDAH) tiene factores etiológicos genéticos y ambientales. Hay pocas publicaciones acerca de los factores ambientales. El objetivo de esta revisión es presentar el papel de la adversidad psicosocial en la etiología y el curso del TDAH. Métodos: Se llevó a cabo una búsqueda en las siguientes bases de datos: PubMed, ScienceDi-rect, SciELO, ClinicalKey, EMBASE, Lilacs, OVID, APA y PsycNET. Se seleccionaron artículos en inglés y español sin limitar por tipo de estudio o año de publicación. Finalmente, se hizo una síntesis cualitativa. Resultados: El desarrollo del TDAH podría estar relacionado con la exposición a factores adversos en el entorno familiar, escolar o social. Se ha propuesto como mecanismo explicativo que la adversidad interactúa con variantes genéticas y conduce a cambios neurobiológicos. También puede haber una correlación entre gen y ambiente, en la que las características hereditarias individuales aumentan el riesgo de exposición a la adversidad e indirectamente aumentan la probabilidad de sufrir TDAH. La investigación sobre la adversidad psicosocial representa un gran desafío no solo por la complejidad de su constructo, sino también por el efecto de la percepción subjetiva sobre un evento determinado. Conclusiones: La etiología del TDAH es compleja y factores genéticos y ambientales presentan una interacción en la que estos factores se correlacionan y originan el trastorno. El estudio del papel de la adversidad psicosocial en el TDAH es fundamental, pero sigue siendo una tarea que conlleva grandes dificultades.
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BACKGROUND: Depression is associated with Alzheimer's disease (AD). OBJECTIVE: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population. METHODS: We conducted a retrospective study to identify depressive symptoms among 190 presenilin 1 (PSEN1) E280A mutation carriers, subjected to comprehensive clinical evaluations in up to a 20-year longitudinal follow-up. We controlled for the following potential confounders: APOE, sex, hypothyroidism, education, marital status, residence, tobacco, alcohol, and drug abuse. RESULTS: PSEN1 E280A carriers with depressive symptoms before mild cognitive impairment (MCI) develop dementia faster than E280A carriers without depressive symptoms (Hazard Ratio, HRâ=â1.95; 95% CI, 1.15-3.31). Not having a stable partner accelerated the onset of MCI (HRâ=â1.60; 95 % CI, 1.03-2.47) and dementia (HRâ=â1.68; 95 % CI, 1.09-2.60). E280A carriers with controlled hypothyroidism had later age of onset of depressive symptoms (HRâ=â0.48; 95 % CI, 0.25-0.92), dementia (HRâ=â0.43; 95 % CI, 0.21-0.84), and death (HRâ=â0.35; 95 % CI, 0.13-0.95). APOEÉ2 significantly affected AD progression in all stages. APOE polymorphisms were not associate to depressive symptoms. Women had a higher frequency and developed earlier depressive symptoms than men throughout the illness (HRâ=â1.63; 95 % CI, 1.14-2.32). CONCLUSION: Depressive symptoms accelerated progress and faster cognitive decline of autosomal dominant AD. Not having a stable partner and factors associated with early depressive symptoms (e.g., in females and individuals with untreated hypothyroidism), could impact prognosis, burden, and costs.
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Doença de Alzheimer , Disfunção Cognitiva , Feminino , Humanos , Masculino , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Apolipoproteínas E/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico , Depressão/epidemiologia , Depressão/genética , Progressão da Doença , Estudos RetrospectivosRESUMO
Currently, transcranial stimulation for CVA treatment is based on the interhemispheric rivalry model. This model has proven to have many anomalies, necessitating a new paradigm. Spontaneous recovery from post-CVA hemiplegia has an ontogenetic pattern. We reanalyzed the 2008 longitudinal London study and found that cortical disinhibition is the mechanism for ontogenetic CVA recovery. We propose that transcranial stimulation with 10 Hz rTMS or anode electrical microstimulation can produce CVA recovery similar to spontaneous recovery. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2466).
Actualmente la aplicación de la estimulación transcraneal para el tratamiento del ACV se realiza con base en el modelo de rivalidad interhemisférica. Este modelo ha mostrado muchas anomalías que hacen necesario un nuevo paradigma. La recuperación espontánea de la hemiplejia post-ACV tiene patrón ontogénico. Reanalizamos el estudio longitudinal de Londres 2008 y encontramos que su propuesta corresponde al mecanismo de recuperación ontogénica del ACV. Planteamos que la estimulación transcraneal, utilizando EMTr a 10 Hz o microestimulación eléctrica anódica, podría recuperar el ACV de manera similar a la recuperación espontánea. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2466).
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C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.
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Oxirredutases do Álcool , Proteínas Correpressoras , Hipotonia Muscular , Fatores de Transcrição , Humanos , Oxirredutases do Álcool/genética , Ataxia/genética , Proteínas Correpressoras/genética , Hipotonia Muscular/genética , Mutação , Mutação de Sentido Incorreto , Fatores de Transcrição/genéticaRESUMO
Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade , Receptores Acoplados a Proteínas G , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Polipeptídeo Inibidor Gástrico/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Genômica , Glucose , Humanos , Incretinas/genética , Incretinas/metabolismo , Neurogênese , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos , SecretinaRESUMO
INTRODUCTION: By 2021, the American College of Medical Genetics and Genomics (ACMG) published the last version of their secondary findings (SF) reporting recommendations for cases in which a person receives a genetic test. OBJECTIVE: To determine in a sample of the Colombian population the prevalence of SF for the 59 genes on the ACMG SF v2.0 list associated with 27 genetic diseases. MATERIALS AND METHODS: An analytical cross-sectional study was developed by examining the sequences of 160 exomes. Based on the ACMG guidelines, a variant classification algorithm was designed to filter and select reportable SF. RESULTS: Eleven pathogenic variants were identified in 13/160 (8.13%) patients in genes APOB, BRCA2, CACNA1S, COL3A1, LDLR, MYBPC3, PCSK9, PKP2, PMS2 and RYR2. No association was found between the sociodemographic variables and the SF to report (P > 0,05). CONCLUSION: We reported the first approach of actionable pathogenic variants spectrum in the Colombian population. Given the frequency found in this study and the clinical impact of genomic variants on health, it is essential to actively search for SF having the opportunity to receive genetic counselling, prevention and clinical management.
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Testes Genéticos , Pró-Proteína Convertase 9 , Colômbia/epidemiologia , Estudos Transversais , Atenção à Saúde , Variação Genética , Humanos , Pró-Proteína Convertase 9/genética , Estados UnidosRESUMO
A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.
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Abstract A patient with chronic brainstem CVA sequelae received one cycle of magnetic stimulation to treat her dysphagia and serendipitously obtained a minimal improvement in her axial movement. Two additional cycles gave her improved postural control and then distal movement, preceded by a display of ipsilateral and contralateral motor evoked potentials, respectively. Magnetic stimulation at 10 Hertz produces cortical disinhibition and reopens the critical neurodevelop ment periods. The ontogenic pattern of hemiplegia recovery in this patient may be explained by an increased and rejuvenated brain plasticity due to critical period reopening through cortical disinhibition. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2253).
Resumen Una paciente con secuelas crónicas de un ACV del tallo cerebral recibió un ciclo de estimulación magnética para el manejo de la disfagia y, por serendipia obtuvo mejoría leve del movimiento axial. Dos ciclos adicionales le permitieron mejoría del control postural y luego la aparición de movimiento distal, precedidos por la visualización de los potenciales evocados motores ipsilateral y contralateral, respectivamente. La estimulación magnética a 10 Hertz produce desinhibición cortical y reabre los periodos críticos del neurodesarrollo. Es posible, que el patrón ontogénico de recuperación de la hemiplejía en esta paciente se explique por el incremento y rejuvenecimiento de la plasticidad cerebral debido a la reapertura de los periodos críticos, por medio de la desinhibición cortical. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2253).