Autism spectrum disorder (ASD) is characterized by impairments in reciprocal social interaction and communication, and by restricted and repetitive behaviors. Family studies indicate a significant ...genetic basis for ASD susceptibility, and genomic scanning is beginning to elucidate the underlying genetic architecture. Some 5–15% of individuals with ASD have an identifiable genetic etiology corresponding to known chromosomal rearrangements or single gene disorders. Rare (<1% frequency) de novo or inherited copy number variations (CNVs) (especially those that affect genes with synaptic function) are observed in 5–10% of idiopathic ASD cases. These findings, coupled with genome sequencing data suggest the existence of hundreds of ASD risk genes. Common variants, yet unidentified, exert only small effects on risk. Identification of ASD risk genes with high penetrance will broaden the targets amenable to genetic testing; while the biological pathways revealed by the deeper list of ASD genes should narrow the targets for therapeutic intervention.
A copy number variation map of the human genome Zarrei, Mehdi; MacDonald, Jeffrey R; Merico, Daniele ...
Nature reviews. Genetics,
03/2015, Letnik:
16, Številka:
3
Journal Article, Book Review
Recenzirano
Odprti dostop
A major contribution to the genome variability among individuals comes from deletions and duplications - collectively termed copy number variations (CNVs) - which alter the diploid status of DNA. ...These alterations may have no phenotypic effect, account for adaptive traits or can underlie disease. We have compiled published high-quality data on healthy individuals of various ethnicities to construct an updated CNV map of the human genome. Depending on the level of stringency of the map, we estimated that 4.8-9.5% of the genome contributes to CNV and found approximately 100 genes that can be completely deleted without producing apparent phenotypic consequences. This map will aid the interpretation of new CNV findings for both clinical and research applications.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
A genetic basis for autism spectrum disorder (ASD) is now well established, and with the availability of high‐throughput microarray and sequencing platforms, major advances have been made in our ...understanding of genetic risk factors. Rare, often de novo, copy number and single nucleotide variants are both implicated, with many ASD‐implicated genes showing pleiotropy and variable penetrance. Additionally, common variants are also known to play a role in ASD's genetic etiology. These new insights into the architecture of ASD's genetic etiology offer opportunities for the identification of molecular targets for novel interventions, and provide new insight for families seeking genetic counselling.
What the paper adds
A number of rare genetic variants are implicated in autism spectrum disorder (ASD), with some showing recurrence.
Common genetic variants are also important and a number of loci are now being uncovered.
Genetic testing for individuals with ASD offers the opportunity to identify relevant genetic etiology.
Resumen
Progreso en la genética del trastorno del espectro autista
Actualmente se ha establecido una base genética para el trastorno del espectro autista (TEA) y, con la disponibilidad de plataformas de secuenciación y microarrays de alto rendimiento, se han logrado avances importantes en nuestra comprensión de los factores de riesgo genéticos. Raras, a menudo de novo, número de copias y variantes de nucleótido único están implicadas, con muchos genes implicados en TEA que muestran pleiotropía y penetrancia variable. Además, también se sabe que las variantes comunes desempeñan un papel en la etiología genética de TEA pero aún no se han identificado. Estos nuevos conocimientos sobre la arquitectura de la etiología genética de TEA ofrecen oportunidades para la identificación de objetivos moleculares para intervenciones novedosas, y proporcionan una nueva perspectiva para las familias que buscan asesoramiento genético.
Resumo
Progresso na genética do transtorno do espectro autista
Uma base genética para o transtorno do espectro autista (TEA) agora está bem estabelecida, e com a disponibilidade de plataformas de microarray de larga escala e de sequenciamento, grandes avanços têm sido feitos para a compreensão dos fatores de risco genéticos. Variantes raras, frequentemente de novo, tanto de cópia extra quanto de nucleotídeos simples têm sido implicadas, com muitos genes relacionados ao TEA mostrando pleiotropia e penetrância variável. Adicionalmente, sabe‐se que variantes comuns também desempenham um papel na etiologia genetica do TEA, mas ainda precisam ser identificadas. Estas novas descobertas sobre a arquitetura da etiologia genética do TEA oferecem oportunidades para a identificação de alvos moleculares para novas intervenções, e fornecem novas possibilidades para famílias procurando aconselhamento genético.
What the paper adds
A number of rare genetic variants are implicated in autism spectrum disorder (ASD), with some showing recurrence.
Common genetic variants are also important and a number of loci are now being uncovered.
Genetic testing for individuals with ASD offers the opportunity to identify relevant genetic etiology.
This article's has been translated into Spanish and Portuguese.
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Over the past decade, the Database of Genomic Variants (DGV; http://dgv.tcag.ca/) has provided a publicly accessible, comprehensive curated catalogue of structural variation (SV) found in the genomes ...of control individuals from worldwide populations. Here, we describe updates and new features, which have expanded the utility of DGV for both the basic research and clinical diagnostic communities. The current version of DGV consists of 55 published studies, comprising >2.5 million entries identified in >22,300 genomes. Studies included in DGV are selected from the accessioned data sets in the archival SV databases dbVar (NCBI) and DGVa (EBI), and then further curated for accuracy and validity. The core visualization tool (gbrowse) has been upgraded with additional functions to facilitate data analysis and comparison, and a new query tool has been developed to provide flexible and interactive access to the data. The content from DGV is regularly incorporated into other large-scale genome reference databases and represents a standard data resource for new product and database development, in particular for copy number variation testing in clinical labs. The accurate cataloguing of variants in DGV will continue to enable medical genetics and genome sequencing research.
It is unclear how disease mutations impact intrinsically disordered protein regions (IDRs), which lack a stable folded structure. These mutations, while prevalent in disease, are frequently neglected ...or annotated as variants of unknown significance. Biomolecular phase separation, a physical process often mediated by IDRs, has increasingly appreciated roles in cellular organization and regulation. We find that autism spectrum disorder (ASD)- and cancer-associated proteins are enriched for predicted phase separation propensities, suggesting that IDR mutations disrupt phase separation in key cellular processes. More generally, we hypothesize that combinations of small-effect IDR mutations perturb phase separation, potentially contributing to “missing heritability” in complex disease susceptibility.
Could mutations that alter protein phase separation properties, but not structure, potentially explain some of the “missing heritability” in complex disease susceptibility?
Among medical disciplines, diagnosis in psychiatry depends highly upon descriptive signs and symptoms, rather than biomarkers. Clear descriptions of specific genetic etiologies have been lacking; ...genomic technologies, however, are rapidly changing that landscape. Notably, chromosomal microarrays—which detect gene copy number variants (CNVs)—are a recommended standard of care for neurodevelopmental disorders. As a result, an increasing number of patients now receive a clinical diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and an identified genetic etiological variant. However, psychiatric and genetic diagnoses are frequently communicated and managed as two disconnected diagnostic parameters. Here, we advocate for a transition model, allowing the integration of genetic etiological information—starting with diagnostically proven CNVs—within the DSM-5 classification framework.
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic ...heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived ...for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in
SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of
SHANK3 to the ...pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional
SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of
SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.
Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain ...the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT reference: (CAG)n-CAA-CAG, since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region (CAG)n-CAG-CAG. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36–39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.
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