Rapid progress in identifying the genes underlying autism spectrum disorder (ASD) has provided the substrate for a first wave of analyses into the underlying neurobiology. This review describes the ...consensus across these diverse analyses, highlighting two distinct sets of genes: 1) Genes that regulate chromatin and transcription, especially in cortical projection neurons and striatal medium spiny neurons during mid-fetal development; and 2) Genes involved in synapse development and function, especially during infancy and early childhood, and differentially expressed in the post mortem ASD brain. Both gene sets are also regulatory targets of the ASD genes CHD8 and FMRP . It remains to be seen whether these represent two independent paths to the ASD phenotype or two components of a common path.
Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one ...affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio OR = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.
Technological advances have enabled high-throughput omics assays, such as parallelized screening of lipids across plasma samples. Pioneering a new paradigm for neuropsychiatric biomarker discovery, ...Yap et al. describe a large-scale systematic analysis of comprehensive phenotypic, genotypic, environmental, and lipidomic data to unravel the intricate interplay between these and autism-associated traits.
Technological advances have enabled high-throughput omics assays, such as parallelized screening of lipids across plasma samples. Pioneering a new paradigm for neuropsychiatric biomarker discovery, Yap et al. describe a large-scale systematic analysis of comprehensive phenotypic, genotypic, environmental, and lipidomic data to unravel the intricate interplay between these and autism-associated traits.
Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, ...a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.
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•Protein truncation in SCN2A/NaV1.2 bears considerable autism spectrum disorder risk•NaV1.2 governs action potential initiation in immature neocortical pyramidal cells•Mature Scn2a+/− neurons have impaired dendritic excitability and excitatory synapses•Cell-autonomous loss of NaV1.2 in mature cells alone impairs synaptic function
Haploinsufficiency in the gene SCN2A, which encodes the sodium channel NaV1.2, has strong autism association. Spratt et al. show that Scn2a contributes to dendritic excitability in mature neocortical pyramidal cells, where its loss impairs excitatory synaptic function and plasticity.
The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we ...describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of noncoding genetic variants that cause cryptic splicing. Synonymous and intronic mutations with predicted splice-altering consequence validate at a high rate on RNA-seq and are strongly deleterious in the human population. De novo mutations with predicted splice-altering consequence are significantly enriched in patients with autism and intellectual disability compared to healthy controls and validate against RNA-seq in 21 out of 28 of these patients. We estimate that 9%–11% of pathogenic mutations in patients with rare genetic disorders are caused by this previously underappreciated class of disease variation.
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•SpliceAI, a 32-layer deep neural network, predicts splicing from a pre-mRNA sequence•75% of predicted cryptic splice variants validate on RNA-seq•Cryptic splicing may yield ∼10% of pathogenic variants in neurodevelopmental disorders•Cryptic splice variants frequently give rise to alternative splicing
A deep neural network precisely models mRNA splicing from a genomic sequence and accurately predicts noncoding cryptic splice mutations in patients with rare genetic diseases.
De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ...ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.
Autism spectrum disorder (ASD) is a common disorder that causes substantial distress. Heritability studies consistently show a strong genetic contribution, raising the hope that identifying ...ASD-associated genetic variants will offer insights into neurobiology and ultimately therapeutics. Next-generation sequencing (NGS) enabled the identification of disruptive variants throughout protein-coding regions of the genome. Alongside large cohorts and novel statistical methods, these NGS methods revolutionized ASD gene discovery. NGS methods have also contributed substantially to functional genetic data, such as gene expression, used to understand the neurobiological consequences of disrupting these ASD-associated genes. These functional data are also critical for annotating the noncoding genome as whole-genome sequencing (WGS) begins to provide initial insights outside of protein-coding regions. NGS methods still have a major role to play, as do similarly transformative advances in stem cell and gene-editing methods, in translating genetic discoveries into a first generation of ASD therapeutics.
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric ...symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians ...caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti–glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.
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