Understanding rare variant contributions to autism: lessons from dystrophin-deficient model

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Costa, Claudia Ismania Samogy ; Madanelo, Luciana ; Wang, Jaqueline Yu Ting ; Campos, Gabriele da Silva ; Girardi, Ana Cristina De Sanctis ; Scliar, Marilia ; Monfardini, Frederico ; Pavanello, Rita de Cassia Mingroni ; Coria, Vivian Romanholi ; Vibranovski, Maria Dulcetti ; Krepischi, Ana Cristina ; Lourenco, Naila Cristina Vilaca ; Zatz, Mayana ; Yamamoto, Guilherme Lopes ; Zachi, Elaine Cristina ; Passos-Bueno, Maria Rita

• Tipo de documento: Artigo Científico
• Fonte: NPJ GENOMIC MEDICINE; v. 10, n. 1, p. 12-pg., 2025-03-06.

Resumo

Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000-6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; similar to 20%) and intellectual disability (ID; similar to 30%). However, their low penetrance in dystrophinopathies suggests additional contributing factors. In our study, 83 individuals with dystrophinopathies were clinically evaluated and categorized based on ASD (36 individuals), ID risk (12 individuals), or controls (35 individuals). Exome sequencing analysis revealed an enrichment of risk de novo variants (DNVs) in ASD-DMD individuals (adjusted p value = 0.0356), with the number of DNVs correlating with paternal age (p value = 0.0133). Additionally, DMD-ASD individuals showed a higher average of rare risk variants (RRVs) compared to DMD-Controls (adjusted p value = 0.0285). Gene ontology analysis revealed an enrichment of extracellular matrix-related genes, especially collagens, and Ehlers-Danlos syndrome genes in ASD-DMD and DMD-ID groups. These findings support an oligogenic model for ASD in dystrophinopathies, highlighting the importance of investigating homogenized samples to elucidate ASD's genetic architecture. (AU)

• Processo FAPESP: 14/50931-3 - INCT 2014 - Envelhecimento e Doenças Genéticas: Genômica e Metagenômica
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/19521-7 - Caracterização da arquitetura genética de doenças de neurodesenvolvimento utilizando como modelo a Distrofia Muscular de Duchenne
• Beneficiário: Claudia Ismania Samogy Costa
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 23/01887-0 - Investigação de mecanismos epigenéticos na etiologia do Transtorno do Espectro Autista em distrofinopatias
• Beneficiário: Gabriele da Silva Campos
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto