Three generation families: Analysis of de novo variants in autism

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Costa, Claudia I. Samogy ; Campos, Gabriele da Silva ; Montenegro, Eduarda Morgana da Silva ; Wang, Jaqueline Yu Ting ; Scliar, Marilia ; Monfardini, Frederico ; Zachi, Elaine Cristina ; Lourenco, Naila C. V. ; Chan, Ada J. S. ; Pereira, Sergio L. ; Engchuan, Worrawat ; Thiruvahindrapuram, Bhooma ; Zarrei, Mehdi ; Scherer, Stephen W. ; Passos-Bueno, Maria Rita

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Human Genetics; v. 31, n. 9, p. 6-pg., 2023-06-06.

Resumo

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts. The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size. These results further reinforce the relevance of de novo variants in ASD. (AU)

• 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: 18/13743-5 - Análise de big data de variantes genômicas em indivíduos com transtorno do espectro autista e validação de novos genes candidatos
• Beneficiário: Eduarda Morgana da Silva Montenegro Malaguti de Souza
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 17/05824-2 - Investigação de alterações de novo de risco em país de pacientes com o Transtorno do Espectro Autista
• Beneficiário: Eduarda Morgana da Silva Montenegro Malaguti de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado