It is found that damaging de novo single-nucleotide variants and frameshift indels explain 3.4% (95% CI: 2.1% - 4.7%) of autism variance on the observed scale.
Abstract
De novo mutations in protein-coding regions are strongly associated with autism, and family-based sequencing studies have identified numerous genes that harbor excess mutations in probands. However, the aggregate contribution of this class of variation to autism remains unclear. Here, we model the distribution of de novo autosomal coding variant effect sizes in 38,680 autism trios to estimate fundamental features of de novo genetic architecture. We find that damaging de novo single-nucleotide variants and frameshift indels explain 3.4% (95% CI: 2.1% - 4.7%) of autism variance on the observed scale. Approximately 7.0% (95% CI: 5.6% - 8.4%) of cases carry a large-effect mutation (rate ratio > 5), and most such mutations are incompletely penetrant. Although hundreds of genes make some nonzero contribution, 50% of mutational variance on the autosomes is explained by just 15 genes. De novo enrichments vary across cohorts with different ascertainment strategies; making projections for future trio studies, we show that many large-effect genes remain to be found.
PURPOSE OF REVIEW
This paper covers some of the key findings on the topic of genetic influences in autism over the last 12-18 months, which consist of significant conceptual shifts and new insights from recent technological advances.
RECENT FINDINGS
Autism is a highly heritable condition, with significant heterogeneity of the genes that influence the development of this condition. The heterogeneity of autism, and multiple pathways contributing to the development of an autistic phenotype, create challenges in our understanding, diagnosis, and management of this condition.Recent studies of common genetic variation and polygenic risk scores have focussed on resolving phenotypic heterogeneity and identifying meaningful autism subtypes. Rare-variant discovery has expanded across ancestries, the X chromosome, noncoding loci, structural variants, and tandem repeats, aided by long-read and pangenome-informed sequencing. Single-cell multiomics, spatial perturbation methods and human organoid models have connected genetic variation to cell-type-specific and developmental phenotypes, while also revealing substantial mutation-specific effects and methodological sensitivity. Genetic testing increasingly provides aetiological diagnoses and informs medical surveillance. Recent developments also illustrate the therapeutic potential of gene-first approaches for selected monogenic neurodevelopmental disorders.
SUMMARY
Recent developments have expanded our understanding of the way the genetic basis of autism manifests phenotypically.
V. Eapen, A. Stylianakis, I. Voineagu· Current Opinion in Psychiatr...· 0 citations
This study finds that rare variants across hundreds of genes contribute to autism with variable phenotypic outcomes, and clusters them based on association evidence from large-scale studies of developmental disorders, schizophrenia, bipolar disorder, and epilepsy.
F. Satterstrom, C. Auwerx, J.-M. Fu et al.· medRxiv· 0 citations
Increased CNV burden, in both number and cumulative genomic size, co-occurred more frequently in individuals with severe phenotypes, including ASD with intellectual disability, epilepsy, and broader NDDs, reflecting a real-world clinical setting rather than a prospectively recruited research cohort.
M. R. Di Iorio, Ilaria La Monica, Antonio Imperatore et al.· International Journal of Mol...· 0 citations
Ongoing need for chromosome microarray analysis (CMA) characterization prompted the description of all 16,138 copy number variants (CNVs) found in 3832 patients studied from 2009 to 2024, 92% of them with developmental disabilities and/or autism. Detailed reporting shows the overlap of variants qualified as benign (15,083 CNVs, sizes 0.1 Kb–3 Mb) or of uncertain significance (216 CNVs, sizes 11 Kb–20 Mb) with pathogenic CNVs (836, 11 Kb–31 Mb), which are emphasized in most studies. Further distinguishing pathogenic CNVs were 88 recurring microdeletion/duplications and 86 in single patients, with all of the former and 66 of the latter having previous syndrome associations. Diagnoses were provided in 749 (20% of) patients, increasing to 21% among the 2470 patients (2015–2024) with their karyotypes recorded. Diagnoses included 61 known chromosomal syndromes, with CMA confirming or clarifying the abnormal karyotype in 187 (7.6%) or 55 (2.2%). The 90 microdeletions averaged 6439 kb in length (with chromosomes 6, 8, 17, and 22 accounting for most cases), while the 90 microduplications averaged 6895 kb (with chromosomes 8, 14, 17, 22, and X accounting for most cases). Together, these represent an average imbalance of 798,000 nucleotides per patient (0.75% of their genome). Continued reporting that match detailed CNV findings with patient profiles, especially symptom spectra, is needed to optimize CMA potential for presymptomatic diagnosis and therapy.
Santosh Chaval, Sahil S. Tonk, Golder N. Wilson et al.· Current Issues in Molecular...· 0 citations
Abstract Genomic studies of autism spectrum disorder (ASD) have largely excluded admixed populations. To address this gap, we characterized the genomic landscape of ASD in Brazil by combining a systematic literature review with whole-exome sequencing analysis of 441 Brazilian individuals and their families. Our analysis revealed a conclusive molecular diagnosis in 13.1% of probands. The diagnostic yield was higher among individuals with clinical features, particularly comorbid signs of intellectual disability, hypotonia, and seizures, providing a basis for prioritizing genetic testing. The sample presented a diverse ancestry, with major European, African, and Native American contributions. Notably, more than half of the identified rare risk variants were located on non-European haplotypes. Both de novo and inherited variants contributed to ASD risk, and we reinforce NPAS3 as a candidate ASD risk gene. This study provides the first comprehensive genomic overview of ASD in a large Brazilian cohort, reinforcing the critical need to include diversely admixed populations in genomic research to expand the understanding of ASD architecture and improve diagnostic strategies in resource-limited settings.
Gabriele da Silva Campos, C. I. S. Costa, J. Wang et al.· Genetics and Molecular Biolo...· 0 citations
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