Genetic Heterogeneity in Autism Spectrum Disorder: Diagnostic Yield, Recurrent Genes, and Rare Variant-Phenotype Associations from Whole-Exome Sequencing

Contribution of Copy Number Variants and Cumulative Genetic Load to Autism Spectrum Disorders: Integrative Insights from Chromosomal Microarray Analysis

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.

Rare variation illuminates the distinct and pleiotropic genetic architecture of autism across neuropsychiatric traits

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.

Diagnostic Yield of Whole Exome Sequencing in Autism Spectrum Disorder Patients at a Tertiary Center in Saudi Arabia.

Discovery of Causative Genetic Variants in Patients with Congenital and/or Developmental Anomalies by Exome Sequencing

This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases.

Chromosomal Microarray Diagnostic Yield and Copy Number Variants in a Clinically Well-Characterized Cohort with Nonsyndromic Autism Spectrum Disorder from Southern Brazil

Background/Objectives: Chromosomal microarray analysis (CMA) is widely used in the genetic evaluation of autism spectrum disorder (ASD), yet its diagnostic contribution in clinically nonsyndromic ASD, particularly in Brazilian populations, remains insufficiently characterized. This study aimed to determine the diagnostic yield of CMA and characterize clinically relevant copy number variants (CNVs) in a cohort of individuals with clinically nonsyndromic ASD from southern Brazil. Methods: In this observational cohort study, 215 individuals with clinically diagnosed ASD underwent high-resolution CMA using the Agilent CGH + SNP Array 180K platform. Individuals with dysmorphic features, known or suspected genetic syndromes, major congenital malformations, epilepsy, or macrocephaly/microcephaly were excluded. CNVs were classified according to American College of Medical Genetics and Genomics guidelines, and the diagnostic yield was compared with that of national and international reference cohorts using Fisher’s exact test. Results: Pathogenic or likely pathogenic CNVs were identified in six individuals, corresponding to a diagnostic yield of 2.8% (95% CI, 1.3–6.1%). These included deletions at 2q11.1–q11.2, 2p16.3 (NRXN1), 15q11.2 (BP1–BP2), and 3q29, and duplications at 16p11.2 and 6p22.3–p22.2. Although the diagnostic yield was lower than that reported in phenotypically heterogeneous ASD cohorts, it did not differ significantly from yields observed in comparably selected nonsyndromic subgroups. Conclusions: CMA identified clinically relevant recurrent CNVs at neurodevelopmental loci even in a clinically nonsyndromic ASD cohort. The comparatively low diagnostic yield highlights the substantial influence of clinical and phenotypic selection on the diagnostic contribution of CMA.

From genotype to phenotype: understanding the genetic basis of autism.

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.