ArticleHuman genetics2023
Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.
Article in Human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
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Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 15 citations in OpenAlex.
- Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease.Human genomics · 2024Pooled it
- Targeting MAPK Pathways in Skin, Thyroid, and Pancreatic Cancer: A Perspective on Synthetic Inhibitors and Natural Modulators.Advanced biology · 2026Review
- Combined biochemical profiling and DNA sequencing in the expanded newborn screening for inherited metabolic diseases: the experience in an Italian reference center.Orphanet journal of rare diseases · 2025Article
- Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.The Journal of pharmacology and experimental therapeutics · 2024Review
- Effects of MAP4K inhibition on neurite outgrowth.Molecular brain · 2023Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.