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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.

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.

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

Background Recent studies in bipolar offspring (BO) showed that a low cognitive performance, especially executive function deficit, could be an early marker of bipolar disorder (BD). Nevertheless, these findings have not been replicated (specifically attentional control, flexibility, and working memory). In addition, most studies have focused on children and adolescents, but few studies analyze the executive function performance in BO adults. Objective Our goal was to compare the neurocognitive performance of BO with control parent-offspring (CO) in a sample that included various age groups. Method We conducted a cohort study, including subjects between six to 30 years old. We evaluated 129 BO and 113 CO subjects using validated psychiatric diagnostic interviews and an extensive neuropsychological battery. Results Compared to the CO group, the BO group presented a lower performance in several executive functioning domains, mainly in tasks of attentional control, flexibility, and working memory. All age groups exhibited these findings. Conclusions BO group presents executive function deficits, regardless of the age group: children, adolescents, and adults. This neurocognitive deficit should be accountable as a neurocognitive endophenotype candidate in BD.

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.

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 espontanea de la hemiplejia post- ACV tiene patrón ontogénico. Reanalizamos el estudio longitudinal de Londres 2008 y encontramos que la desinhibición cortical corresponde al mecanismo de recuperación ontogénica del ACV. Planteamos que la estimulación transcraneal, utilizando EMTr a 10 Hz o microestimulación eléctrica anódica, puede recuperar el ACV de manera similar a la recuperación espontánea.

A whole-exome capture and next-generation sequencing applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, severe cognitive deficit, without any identifiable Syndromic pattern, and to her parents, 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 to 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 one, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURA WT and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural confor-mation in the ~5Å 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 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 indices 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 paves 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.

Contains fulltext : 237889.pdf (Publisher’s version ) (Open Access) The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = -2.701; p = 0.0069); rs1947274 A allele (Z score = -2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = -0.822; p = 0.4109); and rs2345039 C allele (Z score = -1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3's role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD.

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

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.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.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.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).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.

Temporal processing (TP) is associated with functions such as perception, verbal skills, temporal perspective, and future planning, and is intercorrelated with working memory, attention, and inhibitory control, which are highly impaired in individuals with attention deficit hyperactivity disorder (ADHD). Here we evaluate TP measures as potential endophenotypes in Caribbean families ascertained from probands affected by ADHD. A total of 232 individuals were recruited and clinically evaluated using an extensive battery of neuropsychological tasks and reaction time (RT)-based task paradigms. Further, the heritability (genetic variance underpinning phenotype) was estimated as a measure of the genetics apportionment. A predictive framework for ADHD diagnosis was derived using these tasks. We found that individuals with ADHD differed from controls in neuropsychological tasks assessing mental control, visual-verbal memory, verbal fluency, verbal, and semantic fluency. In addition, TP measures such as RT, errors, and variability were also affected in individuals with ADHD. Moreover, we determined that only omission and commission errors had significant heritability. In conclusion, we have disentangled omission and commission errors as possible TP endophenotypes in ADHD, which can be suitable to assess the neurobiological and genetic basis of ADHD. A predictive model using these endophenotypes led to remarkable sensitivity, specificity, precision and classification rate for ADHD diagnosis, and may be a useful tool for patients’ diagnosis, follow-up, and longitudinal assessment in the clinical setting.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.

Editorial

Alzheimer’s disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD.

Uveitis, defined as inflammation of the uveal tract of the eye, is a leading cause of blindness and visual impairment throughout the world. The etiology of uveitis is complex, and autoimmunity plays a major role in its pathogenesis. Intermediate uveitis (IU), a subtype of ocular inflammation, has been associated with systemic autoimmune disorders, specifically with multiple sclerosis (MS). This article reports a rare three-generation family with several members affected by IU (four siblings) and comorbid MS (two siblings fulfilling MS diagnostic criteria and a third sibling presenting some neurological symptoms). Based on the clinical findings, we captured and sequenced whole exomes of seven pedigree members (affected and unaffected). Using a recessive model of transmission with full penetrance, we applied genetic linkage analysis to define minimal critical regions (MCRs) in suggestive or nominal regions of linkage. In these MCRs, we defined functional (some pathogenic), novel, and rare mutations that segregated as homozygous in affected and heterozygous in unaffected family members. The genes harboring these mutations, including DGKI, TNFRSF10A, GNGT1, CPAMD8, and BAFF, which are expressed in both eye and brain tissues and/or are related to autoimmune diseases, provide new avenues to evaluate the inherited causes of these devastating autoimmune conditions. © 2019, The Author(s).

Machine learning (ML) algorithms are widely used to develop predictive frameworks. Accurate prediction of Alzheimer’s disease (AD) age of onset (ADAOO) is crucial to investigate potential treatments, follow-up, and therapeutic interventions. Although genetic and non-genetic factors affecting ADAOO were elucidated by other research groups and ours, the comprehensive and sequential application of ML to provide an exact estimation of the actual ADAOO, instead of a high-confidence-interval ADAOO that may fall, remains to be explored. Here, we assessed the performance of ML algorithms for predicting ADAOO using two AD cohorts with early-onset familial AD and with late-onset sporadic AD, combining genetic and demographic variables. Performance of ML algorithms was assessed using the root mean squared error (RMSE), the R-squared (R2), and the mean absolute error (MAE) with a 10-fold cross-validation procedure. For predicting ADAOO in familial AD, boosting-based ML algorithms performed the best. In the sporadic cohort, boosting-based ML algorithms performed best in the training data set, while regularization methods best performed for unseen data. ML algorithms represent a feasible alternative to accurately predict ADAOO with little human intervention. Future studies may include predicting the speed of cognitive decline in our cohorts using ML.

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.

Human Immunodeficiency Virus type 1 (HIV-1) infection is a chronic disease that affects ~40 million people worldwide. HIV-associated neurocognitive disorders (HAND) are common in individuals with HIV-1 Infection, and represent a recent public health problem. Here we evaluate the performance of a recently proposed short protocol for detecting HAND by studying 60 individuals with HIV-1-Infection and 60 seronegative controls from a Caribbean community in Barranquilla, Colombia. The short evaluation protocol used significant neuropsychological tests from a previous study of asymptomatic HIV-1 infected patients and a group of seronegative controls. Brief screening instruments, i.e., the Mini-mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS), were also applied. Using machine-learning techniques, we derived predictive models of HAND status, and evaluated their performance with the ROC curves. The proposed short protocol performs exceptionally well yielding sensitivity, specificity, and overall prediction values &gt, 90%, and better predictive capacity than that of the MMSE and IHDS. Community-specific cut-off values for HAND diagnosis, based on the MMSE and IHDS, make this protocol suitable for HAND screening in individuals from this Caribbean community. This study shows the effectivity of a recently proposed short protocol to detect HAND in individuals with asymptomatic HIV-1-Infection. The application of community-specific cut-off values for HAND diagnosis in the clinical setting may improve HAND screening accuracy and facilitate patients’ treatment and follow-up. Further studies are needed to assess the performance of this protocol in other Latin American populations.

Presenilin-1 (PSEN1) mutations cause familial Alzheimer’s disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype–phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin–proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-020-02249-0.

INTRODUCTION: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. METHOD: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. RESULTS: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR ≤0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycle process. LIMITATIONS: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate, and our cohort was small. Further studies using larger cohorts are warranted. CONCLUSION: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. TRIAL REGISTRATION: Clinicaltrials.gov NCT00265291

Chikungunya virus (CHIKV), a mosquito-borne alphavirus of the Togaviridae family, is part of a group of emergent diseases, including arbovirus, constituting an increasing public health problem in tropical areas worldwide. CHIKV causes a severe and debilitating disease with high morbidity. The first Colombian autochthonous case was reported in the Colombian Caribbean region in September 2014. Within the next two to three months, the CHIKV outbreak reached its peak. Although the CHIKV pattern of clinical symptomatology has been documented in different epidemiological studies, understanding of the relationship between clinical symptomatology and variation in phenotypic response to CHIKV infection in humans remains limited. We performed a cross sectional study following 1160 individuals clinically diagnosed with CHIKV at the peak of the Chikungunya outbreak in the Colombian Caribbean region. We examined the relationship between symptomatology and diverse phenotypic responses. Latent Class Cluster Analysis (LCCA) models were used to characterize patients’ symptomatology and further identify subgroups of individuals with differential phenotypic response. We found that most individuals presented fever (94.4%), headache (73.28%) and general discomfort (59.4%), which are distinct clinical symptoms of a viral infection. Furthermore, 11/26 (43.2%) of the categorized symptoms were more frequent in women than in men. LCCA disclosed seven distinctive phenotypic response profiles in this population of CHIKV infected individuals. Interestingly, 282 (24.3%) individuals exhibited a lower symptomatic “extreme” phenotype and 74 (6.4%) patients were within the severe complex “extreme” phenotype. Although clinical symptomatology may be diverse, there are distinct symptoms or group of symptoms that can be correlated with differential phenotypic response and perhaps susceptibility to CHIKV infection, especially in the female population. This suggests that, comparatively to men, women are a CHIKV at-risk population. Further study is needed to validate these results and determine whether the distinct LCCA profiles are a result of the immune response or a mixture of genetic, lifestyle and environmental factors. Our findings could contribute to the development of machine learning approaches to characterizing CHIKV infection in other populations. Preliminary results have shown prediction models achieving up to 92% accuracy overall, with substantial sensitivity, specificity and accuracy values per LCCA-derived cluster., Author summary The Chikungunya virus (CHIKV) infection is a mosquito-borne virus of the Togaviridae family, part of the arbovirus group of mosquito-transmitted pathogens. CHIKV causes a severe and debilitating disease with high morbidity. In this study, we comprehensively analysed clinical data from 1160 individuals from the Colombian Caribbean, who were diagnosed with CHIKV infection during the 2014 epidemic peak and before the Zika epidemic (registered back in 2015). Further, the presence of latent classes and predictors of CHIKV susceptibility and severity of the CHIKV infection were analysed. Although it is well known that people respond differently to infection, our results showed that these differences are not arbitrary and may come from the specific orchestration of our immune response and specific genetic makeup. For example, we identified that females infected with CHIKV exhibited significant and heterogeneous phenotypic response patterns compared to men. Overall, these results inform about potential predictors and outlining strategies to study the natural history of CHIKV infection. Future studies assessing the contribution of demographic, immunological and genetic factors to symptom co-occurrence could shed some light on the severity of the clinical symptomatology and, ultimately, lead to more accurate, more efficient and differential diagnosis. These results could contribute to the development of machine learning approaches to characterizing CHIKV infection in other populations and provide more accurate and differential diagnosis.

Presented here are five members of a family that was ascertained from an isolated, consanguineous, indigenous Amerindian community in Colombia that was affected with calpain 3-related, limb-girdle muscular dystrophy type R1. These patients are homozygous for a unique and novel deletion of four bases (TGCC) in exon 3 of the calpain 3 gene (CAPN3) (NM_000070.2, NP_000061.1) (g.409_412del). The mutation site occurs at the CysPc protein domain, triggering a modified truncated protein structure and affecting motifs within the calpain-like thiol protease family (peptidase family C2) region. The patients reported here developed a very severe phenotype with primary contractures, spinal rigidity in the early stages of the disease, and bilateral talipes equinovarus (clubfoot) in the most affected patients who had the selective involvement of their extremities&rsquo, distal muscles in a way that resembled Emery&ndash, Dreifuss syndrome. We recommend mandatory screening for calpainopathy in all patients with an Emery&ndash, Dreifuss-like syndrome or those presenting a non-congenital illness with primary contractures and who, because of other data, are suspected of having muscular dystrophy.

Objective: The aim of this study is to contrast the genetics of neuropsychological tasks in individuals from nuclear families clustering ADHD in a Caribbean community. Method: We recruited and clinically characterized 408 individuals using an extensive battery of neuropsychological tasks. The genetic variance underpinning these tasks was estimated by heritability. A predictive framework for ADHD diagnosis was derived using these tasks. Results: We found that individuals with ADHD differed from controls in tasks of mental control, visuospatial ability, visuoverbal memory, phonological and verbal fluency, verbal and semantic fluency, cognitive flexibility, and cognitive ability. Among them, tasks of mental control, visuoverbal memory, phonological fluency, semantic verbal fluency, and intelligence had a significant heritability. A predictive model of ADHD diagnosis using these endophenotypes yields remarkable classification rate, sensitivity, specificity, and precision values (above 80%). Conclusion: We have dissected new cognitive endophenotypes in ADHD that can be suitable to assess the neurobiological and genetic basis of ADHD.

Major depressive disorder (MDD) is a common but serious psychiatric disorder with significant levels of morbidity and mortality. Recent genome-wide association studies (GWAS) on common variants increase our understanding of MDD; however, the underlying genetic basis remains largely unknown. Many studies have been proposed to explore the genetics of complex diseases from a viewpoint of the “missing heritability” by considering low-frequency and rare variants, copy-number variations, and other types of genetic variants. Here we developed a novel computational and statistical strategy to investigate the “missing heritability” of MDD. We applied Hamming distance on common, low-frequency, and rare single-nucleotide polymorphism (SNP) sets to measure genetic distance between two individuals, and then built the multi-dimensional scaling (MDS) pictures. Whole-exome genotyping data from a Los Angeles Mexican-American cohort (203 MDD and 196 controls) and a European-ancestry cohort (473 MDD and 497 controls) were examined using our proposed methodology. MDS plots showed very significant separations between MDD cases and healthy controls for low-frequency SNP set (P value P value = 7.681e−12). Our results suggested that low-frequency and rare variants may play more significant roles in the genetics of MDD.

Los apellidos de origen español, con un modelo de herencia patrilineal, se asemejan a una herencia ligada al cromosoma Y por lo que pueden ser utilizados como marcadores genéticos, y, a su vez, como una metodología preliminar en la determinación de la estructura genética de las poblaciones humanas. En este trabajo fueron analizados los apellidos de 7041 individuos en la población de Granada, Antioquia (Colombia). Se establecieron 203 apellidos diferentes, 100 de los cuales corresponden a los que inicialmente se establecieron en la fundación del pueblo (apellidos fundadores). Los resultados muestran un alto grado de aislamiento en la población. En primer lugar, hubo una correlación significativa entre el estimador B (apellidos más frecuentes) y el coeficiente del parentesco debido a isonimia al azar (θii) (r = 0.88; P < 0.05), lo que indica que gran parte de la variación observada en θii se explica por los siete apellidos más frecuentes. En segundo lugar, se encontró una correlación negativa significativa del estimador B y la riqueza de apellidos (α) (r = -0.92; P < 0.05), que indica aislamiento. Además, la correlación negativa altamente significativa encontrada entre el coeficiente de parentesco debido a isonimia al azar (θii) y la riqueza de apellidos (α) (r = -0.99; P < 0.001), indica un mayor número de uniones entre parientes. Los resultados encontrados confirman el alto grado de subdivisión microevolutiva que había sido detectado mediante el uso de marcadores genéticos clásicos en esta población colombiana. Este método es útil y de bajo costo para el estudio de poblaciones humanas, ya que permite una aproximación inicial a la estructura genética, antes de realizar investigaciones más detalladas con marcadores clásicos. Así, a través de estos primeros análisis los investigadores podrían canalizar objetivos y recursos económicos de una manera más eficaz.

This paper compiles gene frequencies of classical, and DNA genetic markers in order to solve the power of non exclusion of paternity were used. The first way was the Bayesian approach that compute a likelihood ratio of the trio with the putative father as real father versus the trio with the real father as a random male. This likelihood ratio or paternity index can be transformed into a posterior probability if a prior probability of paternity is supplied. The other approach was that of the computation of the probability that a random male would not be excluded by at least one of the tests given the phenotypes of the mother and child. In this case, we carried out the estimation of the paternity index and of the non-exclusion probability. Both of these measures are computed for each locus separately and cumulated over all loci. All analyses are exemplified by using a real example. Finally, we estimated the paternity exclusion probability by using the Ohno et al. equation for each locus with n alleles.

The present study was undertaken to examine the pattern of inheritance of cleft lip and palate (CLP) in pedigrees ascertained from localities belonging to Cundiboyacense altiplano, Colombia. This population has long been known to be the result of the admixture between Amerindian/Spaniard communities five centuries ago. Ninety-eight extended and multigenerational pedigrees, constituted by 125 nuclear components and 651 records were analyzed. Nine hypothetical models were contrasted using likelihood ratio tests. The hypotheses of on no familial transmission, multifactorial component compared against that of the existence of a major gene only, the existence of a recessive major gene, that of non major component in the mixed model and that of the non transmission of major effect (t1 = t2 = t3) were rejected. In contrast, hypotheses postulating a major locus (dominant, codominant) and that of no polygenic component in the mixed model could not be rejected. The major gene model without restrictions in d was the most parsimonious. Thus far, the most parsimonious model is that of a major gene (dominant-codominant) without multifactorial effects. Thus, it must be emphasized that, at least in the Colombian communities, environmental components in predisposing to CLP, as has been pointed out in those hypotheses involving fungicides and some kind of avitaminosis, must be discarded and the genetic mendelian factors must be the focus of research.