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

• Document type: Journal article
• Source: NPJ GENOMIC MEDICINE; v. 10, n. 1, p. 12-pg., 2025-03-06.

Abstract

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)

• FAPESP's process: 14/50931-3 - Aging and genetic disorders: genomics and metagenomics
• Grantee: Mayana Zatz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/19521-7 - Characterization of the genetic architecture of neurodevelopmental disorders using Duchenne Muscular Dystrophy as a model
• Grantee: Claudia Ismania Samogy Costa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/01887-0 - Investigation of epigenetic mechanisms in the etiology of Autism Spectrum Disorder in dystrophinopathies
• Grantee: Gabriele da Silva Campos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)