Whole-Genome Sequencing Reveals a Novel Pathogenic GRIN2B Variant in a Patient with Neurodevelopmental Disorder and an inv(6)(p24p11.2)pat.

INTRODUCTION: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants. Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. CASE PRESENTATION: Here, we describe a NDD patient with a 6p nonpathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. CONCLUSION: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability.

Low-pass whole genome sequencing as a cost-effective alternative to chromosomal microarray analysis for low- and middle-income countries.

Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.

Neurodevelopmental disorder associated with gene ARF3: A case report.

We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy. Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion. Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val). The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature. This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem. It can also manifest as acquired microcephaly and epilepsy. These phenotypic characteristics align with Golgipathies, underscoring the significance of considering this group of conditions in relevant clinical contexts. In cases where a Z-shaped morphology of the brainstem is observed, ARF3-associated disorder should be included in the list of differential diagnoses.

Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder.

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD.

Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3-4% of the world's population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8-21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

A comprehensive review on DDX3X liquid phase condensation in health and neurodevelopmental disorders.

DEAD-box helicases are global regulators of liquid-liquid phase separation (LLPS), a process that assembles membraneless organelles inside cells. An outstanding member of the DEAD-box family is DDX3X, a multi-functional protein that plays critical roles in RNA metabolism, including RNA transcription, splicing, nucleocytoplasmic export, and translation. The diverse functions of DDX3X result from its ability to bind and remodel RNA in an ATP-dependent manner. This capacity enables the protein to act as an RNA chaperone and an RNA helicase, regulating ribonucleoprotein complex assembly. DDX3X and its orthologs from mouse, yeast (Ded1), and C. elegans (LAF-1) can undergo LLPS, driving the formation of neuronal granules, stress granules, processing bodies or P-granules. DDX3X has been related to several human conditions, including neurodevelopmental disorders, such as intellectual disability and autism spectrum disorder. Although the research into the pathogenesis of aberrant biomolecular condensation in neurodegenerative diseases is increasing rapidly, the role of LLPS in neurodevelopmental disorders is underexplored. This review summarizes current findings relevant for DDX3X phase separation in neurodevelopment and examines how disturbances in the LLPS process can be related to neurodevelopmental disorders.

Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

Chromosomal microarray analyses from 5778 patients with neurodevelopmental disorders and congenital anomalies in Brazil.

Chromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 both in the USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity in integrating the results from both the private and public health systems. Although Brazil has one of the world's largest single-payer public healthcare systems, nearly all patients referred for CMA come from the private sector, resulting in only a small number of CMA studies in Brazilian cohorts. To date, this study is by far the largest Brazilian cohort (n = 5788) studied by CMA and is derived from a joint collaboration formed by the University of São Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. We identified 2,279 clinically relevant CNVs in 1886 patients, not including the 26 cases of UPD found. Among detected CNVs, the corresponding frequency of each category was 55.6% Pathogenic, 4.4% Likely Pathogenic and 40% VUS. The diagnostic yield, by taking into account Pathogenic, Likely Pathogenic and UPDs, was 19.7%. Since the rational for the classification is mostly based on Mendelian or highly penetrant variants, it was not surprising that a second event was detected in 26% of those cases of predisposition syndromes. Although it is common practice to investigate the inheritance of VUS in most laboratories around the world to determine the inheritance of the variant, our results indicate an extremely low cost-benefit of this approach, and strongly suggest that in cases of a limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized.

[Genetics of neurodevelopmental disorders. Practical aspects]. / Genética de los trastornos del neurodesarrollo. Aspectos prácticos.

Neurodevelopmental disorders (NDD) constitute a relevant group of pathologies, of childhood, with a biological basis and totally or partially genetic etiology. The recognition of the causal factors constitutes a challenge that has been perfected over the last decades, until obtaining an increasing diagnostic yield. The implementation of these technological advances can only be achieved through the formation of interdisciplinary work teams, which, following an orderly process, achieve a presumptive diagnosis, which is then certified using the techniques that for each of the cases are more profitable in terms of quality and cost. In this paper we list these procedures, based on different scenarios that highlight the extensive menu of possibilities and the need to manage them in a rational way, on well-founded scientific bases.

Los trastornos del neurodesarrollo (TND) constituyen un grupo relevante de enfermedades, con base biológica y etiología total o parcialmente genética. El reconocimiento de los factores causales constituye un reto cuyos resultados se han perfeccionado a lo largo de las últimas décadas, hasta obtener un rédito diagnóstico cada vez mayor. La implementación de estos avances tecnológicos solo puede lograrse mediante la conformación de equipos de trabajo interdisciplinarios, que siguiendo un proceso ordenado, logran un diagnóstico de presunción, que luego es certificado mediante las técnicas que, para cada uno de los casos, resulta más redituable en calidad y costo. En este trabajo, enumeramos estos procedimientos a partir de diferentes escenarios que ponen de relieve el extenso menú de posibilidades y la necesidad de administrar los mismos de un modo racional, sobre bases científicas debidamente fundadas.

[Environmental factors influencing developmental disorders]. / Factores ambientales que influyen en los trastornos del desarrollo.

Neurodevelopmental disorders have been associated with multiple causes especially, genetic a nd environmental -nutritional, infectious, toxic, traumatic and psychosocial stress among others- that in general do not operate alone, but interact with each other. Of special interest is to identify the mechanism(s) that lead to these disorders. Inflammation and epigenetic changes may play a common end for many forms of environmental risk.

Los trastornos del neurodesarrollo, se han asociado con múltiples causas, especialmente genéticas y ambientales ­nutricionales, infecciosas, tóxicas, traumáticas y estrés psicosocial, entre otras­ que en general interactúan entre sí. De especial interés es identificar el/los factores que contribuyen a estos trastornos. Factores ambientales que están relacionados con inflamación y cambios epigenéticos pueden ser una vía común final.

[Neurodevelopmental disorders: from the laboratory to the classroom]. / Desórdenes del neurodesarrollo: del laboratorio al aula de clase.

Neurodevelopmental disorders are the most common diagnosis in the clinical practice in child neurology. Since the 70's the terminology used for the diagnosis of these conditions, was developed with the goal of obtaining better services for those individuals affected. Over the years the classification has changed but the fundamental process for diagnosis continues the same. There is a new movement aiming to change the current classification and propose a new one based in the molecular deficits associated with the clinical phenotype rather than a collection of symptoms. This new approach focusses on the identification of the molecular defectcausing of the specific to design targeted interventions that will promise a curative approach, rather than the current symptom-based interventions available. Important progress has been done alrea dy, given the high association between cognitive/compartmental phenotype in some well-known genetic defects like Neurofibromatosis, TSC, Down syndrome, and the high association between different cognitive/compartmental phenotype in rare diseases. The future will hold opportunities to properly identify the molecular deficit and a tailored intervention for those conditions today called Neurodevelopmental disabilities.

Los desórdenes del Neurodesarrollo son en conjunto los diagnósticos más frecuentes en la práctica clínica en Neurología Infantil. De los años 70', se desarrolló una terminología usada para denominar estos desordenes, con el objetivo de obtener mejor atención en servicios médicos y educativos para los afectados. A lo largo de los años, las clasificaciones han cambiado, pero el proceso fundamental del diagnóstico sigue siendo el mismo. Existe actualmente un movimiento para cambiar y establecer una nueva clasificación, basada en los déficits biológicos asociados con el fenotípico clínico. Esta nueva aproximación diagnóstica tiene como objetivo entre tantos otros, el diseño de intervenciones específicas que prometerían un mayor potencial curativo, a diferencia de las actuales opciones de tratamiento, que se basan en el manejo de síntomas. Importantes progresos se han hecho ya en este campo. Por ejemplo, algunos fenotipos conductuales en condiciones genéticas ampliamente conocidas como el Síndrome de Down, síndrome de X Frágil, neurofibromatosis, esclerosis tuberosa entre otros, han permitido proponer correlaciones biológicas con fenotipos comunes en pacientes con autismo, trastornos por déficit de atención, entre otros. Adicionalmente, el extenso estudio que actualmente se lleva a cabo sobre las denominadas enfermedades raras, que se asocian hasta en un 80% con trastornos del neurodesarrollo, ha abierto la posibilidad para muchas más correlaciones biológicas-comportamentales. En el futuro, será posible esperar oportunidades para la identificación de déficits biológicos moleculares, asociados con fenotipos clínicos cognitivos-conductuales y que, a partir de ellos se puedan diseñar intervenciones individuales a los problemas que hoy conocemos globalmente como los desórdenes del neurodesarrollo.

[New genetic testing algorithm for evaluation of neurodevelopmental disorders]. / Nuevo algoritmo de test genéticos para evaluación de trastornos del neurodesarrollo.

In more than half of neurodevelopmental disorders, a genetic etiology is demonstrated. The detection of these pathogenic variants has a huge impact on the course of the disease of these patients. It allows the acceptance of the disease by the parents of the patients, issue a prognosis, anticipate the future consequences of the disease and in more and more cases establish a treatment or change the one already established. The genetic techniques that allow these etiological diagnoses are very recent therefore not yet fully assumed by neuropediatricians. Even in the diagnostic guides of the different scientific societies, their algorithms are outdated by the quick incorporation of new techniques. This article reviews the current techniques as well as the latest advances in them that are being incorporated into clinical practice.

En más de la mitad de los trastornos del neurodesarrollo se demuestra una etiología genética. La detección de estas variantes patogénicas tiene un impacto enorme en el curso de la enfermedad de estos pacientes. Permite la aceptación de la enfermedad por parte de los padres de los pacientes, emitir un pronóstico, adelantarnos a las futuras consecuencias de la enfermedad y, en cada vez más casos, instaurar un tratamiento o cambiar el ya establecido. Las técnicas genéticas que permiten estos diagnósticos etiológicos son muy jóvenes y por lo tanto todavía no totalmente asumidas por los neuropediatras. Incluso en las guías de diagnóstico de las diferentes sociedades científicas, sus algoritmos están desfasados por la rápida incorporación de nuevas técnicas. En este artículo se revisan las técnicas actuales así como los últimos avances en las mismas, que se están incorporando a la práctica clínica.

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors.

Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)-a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis-represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood-brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location-dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome-environment interactions.

La neuroanatomía y neurofisiología en la comprensión de los trastornos del espectro autista / Neuroanatomy and neurophysiology in the study of autism spectrum disorders

Introducción: Los trastornos de espectro autista se caracterizan por presentar un déficit en la interacción y comunicación social con presencia de patrones repetitivos y restrictivos de comportamiento, intereses y actividades. En ellos estarían implicadas causas genéticas, ambientales y del desarrollo del sistema nervioso central. Un mayor conocimiento de la neuroanatomía y la neurofisiología ayudaría a comprender mejor este trastorno del neurodesarrollo. Objetivo: Profundizar en el conocimiento neuroanatómico y neurofisiológico de los trastornos del espectro autista. Métodos: Se realizó una búsqueda bibliográfica acerca del tema en las bases de datos LILACS, Scopus, SciELO, Pubmed, Medigraphic. Se escogieron 13 documentos, todos correspondientes a artículos originales que abordan el tema desde diferentes aristas. De los documentos, dos fueron localizados en Scopus, uno en Pubmed, cuatro en Medigrafhic, dos en LILACS y cuatro en SciELO. Resultados: Los trastornos de espectro autista se producen por una alteración estructural y funcional de la corteza cerebral. Los estudios de neuroimágenes han demostrado las alteraciones estructurales, fundamentalmente en la corteza prefrontal y sus conexiones, principal región encefálica implicada en la regulación de la conducta social. Las técnicas de secuenciación genómica de nueva generación muestran el origen genético en casos donde los estudios previamente señalados han resultado ser normales. Conclusiones: La profundización del conocimiento neuroanatómico y neurofisiológico de los trastornos de espectro autista permiten comprenderlos mejor(AU)

Introduction: Autism spectrum disorders are characterized by social deficits and communication difficulties, as well as restrictive, repetitive behavior patterns, interests and activities. Their causes may be genetic, environmental or related to the development of the central nervous system. Broader knowledge about neuroanatomy and neurophysiology could lead to a better understanding of this neurodevelopmental disorder. Objective: Gain insight into the neuroanatomy and neurophysiology of autism spectrum disorders. Methods: A bibliographic search about the topic was conducted in the databases LILACS, Scopus, SciELO, Pubmed and Medigraphic. A total 13 documents were selected, all of which were original papers approaching the topic from different perspectives. Two of the documents were obtained from Scopus, one from Pubmed, four from Medigraphic, two from LILACS and four from SciELO. Results: Autism spectrum disorders are caused by a structural and functional alteration of the cerebral cortex. Neuroimaging studies have shown the structural alterations, which mainly occur in the prefrontal cortex and its connections, the principal encephalic region involved in social behavior regulation. New generation genomic sequencing techniques reveal a genetic origin in cases where previous studies have been normal. Conclusions: Broader knowledge about the neuroanatomy and neurophysiology of autism spectrum disorders lead to their better understanding(AU)

Novel USP9X variant associated with syndromic intellectual disability in a female: A case study and review.

Heterozygous variants in USP9X are associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome characterized by neurodevelopmental delay, intellectual disability (ID), and a wide variety of additional congenital anomalies. Here, we report a girl harboring a novel de novo loss-of-function variant in USP9X (c.4091delinsAG, p.Thr1364Lysfs*7), and literature review revealed novel prenatal features associated with MRXS99F, expanding the genotypic and phenotypic landscape of the syndrome. It is important to consider X-linked diseases in girls with ID and perform directed molecular investigation to provide correct diagnosis and prognosis.

Genómica de los trastornos del desarrollo neurológico / Genomics of neurodevelopmental disorders

Introduction: Neurodevelopmental disorders (NDD) are featured by a delay in the acquisition of motor functions, cognitive abilities and speech, or combined deficits in these areas with the onset before the age of 5 years. Genetic causes account for approximately a half of all NDD cases. Objective: to describe alterations of the genome implied in neurodevelopmental disorders and some aspects of their genetic counseling. Methods: Bibliographic search in Medline, Pubmed, Scielo, LILACS and Cochrane, emphasizing in the last five years, the relationship between the various genetic factors that may be involved in neurodevelopmental disorders. Results: Multiple genetic factors are involved in neurodevelopmental disorders, from gross ones such as chromosomal aneuploidies to more subtle ones such as variations in the number of copies in the genome. Special emphasis is placed on microdeletion-micro duplication syndromes as a relatively frequent cause of NDDs and their probable mechanisms of formation are explained. Final Considerations: Genetic aberrations are found in at least 30-50 percent of children with NDD. Conventional karyotyping allows the detection of chromosomal aberrations encompassing more than 5-7 Mb, which represent 5-10 percent of causative genome rearrangements in NDD. Molecular karyotyping (e.g. SNP array/array CGH) can significantly improve the yield in patients with NDD and congenital malformations(AU)

Introducción: Los trastornos del neurodesarrollo están caracterizados por retardo en la adquisición de las funciones motoras, habilidades cognitivas para el habla o el déficit combinado en estas áreas; se presenta en niños menores de 5 años de edad. Las causas genéticas están implicadas en más de la mitad de los pacientes con estos trastornos Objetivo: Examinar las alteraciones del genoma implicados en los trastornos del neurodesarrollo y algunos aspectos de su asesoramiento genético. Métodos: Búsqueda bibliográfica en Medline, Pubmed, Scielo, LILACS y Cochrane con énfasis en los últimos cinco años, acerca de la relación entre los variados factores genéticos que pueden estar involucrados en los trastornos del neurodesarrollo. Resultados: Los factores genéticos involucrados pueden ser groseros como las aneuploidías cromosómicas hasta los más sutiles como las variaciones en el número de copias en el genoma. Se describen los síndromes de microdeleción-micro duplicación como una causa relativamente frecuente de los trastornos del neurodesarrollo y se explican sus probables mecanismos de formación. Se relacionan las aneuploidías cromosómicas y las variaciones en el número de copia como causas de estos trastornos. Consideraciones finales . Las aberraciones genéticas se encuentran en 30-50 por ciento de los niños con trastornos del neurodesarrollo. El cariotipo convencional permite la detección de aberraciones cromosómicas que abarcan más de 5-7 Mb, lo que representa 5-10 por ciento de los reordenamientos genómicos causales en estos trastornos. El cariotipo molecular (por ejemplo, una matriz de SNP/ CGH de matriz) puede mejorar significativamente la certeza del diagnóstico en pacientes con trastornos del neurodesarrollo y malformaciones congénitas(AU)

[Genetic studies and neurodevelopment. From effectiveness to genetic models]. / Estudios genéticos y neurodesarrollo. De la utilidad al modelo genético.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

Estudios genéticos y neurodesarrollo: De la utilidad al modelo genético / Genetic studies and neurodevelopment. From effectiveness to genetic models]

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.