RESUMO
We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.
Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Linhagem , Mapas de Interação de Proteínas/genética , Animais , Criança , Bases de Dados Genéticas , Modelos Animais de Doenças , Feminino , Deleção de Genes , Guanilato Quinases/genética , Humanos , Padrões de Herança/genética , Aprendizado de Máquina , Masculino , Núcleo Familiar , Regiões Promotoras Genéticas/genética , Receptores de Mineralocorticoides/genética , Fatores de Risco , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma , Peixe-Zebra/genéticaRESUMO
The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Adolescente , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Encéfalo , Mapeamento Encefálico , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
A 48-year-old female with no significant past medical history presented to the emergency department with an uncommon scenario after accidentally ingesting a three-unit dental bridge, leading to its impaction within the lower gastrointestinal tract. Despite initial conservative management with laxatives aimed at facilitating spontaneous passage, the foreign body remained lodged in the colon. Subsequently, the patient underwent endoscopic intervention via colonoscopy, during which the dental bridge was successfully extracted. This case highlights the complexity of managing foreign body ingestions, particularly when impaction occurs in uncommon locations, such as the colon. We emphasize the importance of individualized care strategies and recognize the potential of endoscopic procedures in resolving clinical scenarios involving foreign body ingestions.
RESUMO
Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.