Publication
Title
Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome
Author
Abstract
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.
Language
English
Source (journal)
European journal of human genetics / European Society of Human Genetics. - Leiden
Publication
London : Springernature , 2024
ISSN
1018-4813
DOI
10.1038/S41431-024-01556-4
Volume/pages
(2024) , 9 p.
ISI
001173833900001
Pubmed ID
38424297
Full text (Publisher's DOI)
Full text (open access)
The author-created version that incorporates referee comments and is the accepted for publication version Available from 29.08.2024
UAntwerpen
Faculty/Department
Research group
Project info
GENOMED - Genomics in Medicine.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 29.03.2024
Last edited 10.04.2024
To cite this reference