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Eur J Hum Genet ; 32(6): 630-638, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38424297

RESUMO

Mutations in ADNP result in Helsmoortel-Van der Aa syndrome. Here, we describe the first de novo intronic deletion, affecting the splice-acceptor site of the first coding ADNP exon in a five-year-old girl with developmental delay and autism. Whereas exome sequencing failed to detect the non-coding deletion, genome-wide CpG methylation analysis revealed an episignature suggestive of a Helsmoortel-Van der Aa syndrome diagnosis. This diagnosis was further supported by PhenoScore, a novel facial recognition software package. Subsequent whole-genome sequencing resolved the three-base pair ADNP deletion c.[-5-1_-4del] with transcriptome sequencing showing this deletion leads to skipping of exon 4. An N-terminal truncated protein could not be detected in transfection experiments with a mutant expression vector in HEK293T cells, strongly suggesting this is a first confirmed diagnosis exclusively due to haploinsufficiency of the ADNP gene. Pathway analysis of the methylome indicated differentially methylated genes involved in brain development, the cytoskeleton, locomotion, behavior, and muscle development. Along the same line, transcriptome analysis identified most of the differentially expressed genes as upregulated, in line with the hypomethylated CpG episignature and confirmed the involvement of the cytoskeleton and muscle development pathways that are also affected in patient cell lines and animal models. In conclusion, this novel mutation for the first time demonstrates that Helsmoortel-Van der Aa syndrome can be caused by a loss-of-function mutation. Moreover, our study elegantly illustrates the use of EpiSignatures, WGS and Phenoscore as novel complementary diagnostic tools in case a of negative WES result.


Assuntos
Proteínas do Tecido Nervoso , Sítios de Splice de RNA , Humanos , Feminino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pré-Escolar , Células HEK293 , Mutação com Perda de Função , Metilação de DNA , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Transtorno do Espectro Autista , Cardiopatias , Fácies , Transtornos do Neurodesenvolvimento
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