Loss-of-function mutation of the ADNP gene causes Helsmoortel-van der Aa syndrome

Based on the research of Helsmoortel-Van der Aa syndrome (HVDAS) caused by ADNP gene mutations, D’Incal et al. published an in-depth research paper in the European Journal of Human Genetics. Through a case study of a five-year-old girl, the team discovered a three-base pair deletion at the splice acceptor site of the first coding exon of ADNP. This study greatly advanced our understanding of the etiology of HVDAS and demonstrated why previous exome sequencing techniques focusing on gene coding regions had failed in some cases to diagnose the condition.

The research topic was set up based on the core concept that ADNP protein is a key factor in brain development, but how various protein function losses due to ADNP gene mutations act at the pathological level remains unclear. ADNP gene mutations are usually associated with symptoms such as autism, intellectual disability, and developmental delays, so the loss of function or potential effects of mutant proteins play an important role in the occurrence and development of the disease.

The team led by D’Incal et al. includes experts from multiple research institutions, including the University of Antwerp, University Medical Center Utrecht, Amsterdam University Medical Center, and Radboud University Medical Center. This research report was published on February 29, 2024.

The paper details the entire process of a single original research project. The study was divided into multiple steps, including clinical whole-exome sequencing (WES), whole-genome sequencing (WGS), genome-wide CpG methylation analysis, and whole blood transcriptome sequencing. After supplementary exome sequencing failed to detect the deletion variant, genome-wide CpG methylation analysis guided researchers to focus on the splice acceptor site of the ADNP gene, and through in-depth bioinformatics analysis, a three-base pair deletion was discovered.

According to the data obtained, the ADNP protein generated in this study is unique because it regulates gene expression through variations in the splice site. Moreover, transformation experiments used to detect ADNP protein in cells failed to detect the mutant expression vector in HEK293T cells, indicating that the mutant phenotype is entirely caused by haploinsufficiency of the ADNP gene.

After analyzing the variant phenotype caused by ADNP gene mutations, researchers further strengthened the diagnosis using the pathological information identification software Phenoscore. This novel facial recognition technology provides a complementary tool for diagnosis, especially when standard exome sequencing results are negative.

The study highlights the possibility of diagnosing HVDAS through new experimental methods. The paper’s methylation and gene expression analysis for subtype classification revealed disease evolution pathways between different pathogenic regions and demonstrated the importance of understanding and treating this complex neurodevelopmental disorder.

The research by D’Incal et al. provides new strategies for diagnosing HVDAS, especially in detecting non-coding regions. Moreover, the study also supplements the importance of whole-genome sequencing, surface recognition, and epigenetic analysis techniques in diagnosis. This research work proposes to the scientific community possible links between ADNP gene mutations and protein function loss, provides precise explanations of disease mechanisms, and offers important references for future diagnosis and treatment of related diseases.