Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch‐up Development
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OBJECTIVE: Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology. METHODS: We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER. RESULTS: All 9 individuals harbored heterozygous null-allele variants in CUX1, encoding the Cut-homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age-related intelligence at ages 4, 6, and 8 years after a previous history of significant DD. INTERPRETATION: Our results suggest that null-allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch-up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200-207.
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Exploratory analyses show two differentially methylated sites significantly associated with both only cannabis use and cannabis with tobacco, which are within the MARC2 gene and within the CUX1 gene.
“Moreover, these exploratory analyses show two differentially methylated sites significantly associated with both only CU and cannabis with tobacco, which are within the MARC2 gene. The latter previously linked to adverse effects to antipsychotics in schizophrenia (Åberg et al., 2010) and within the CUX1 gene which is involved in neuronal development (Platzer et al., 2018).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Platzer et al., 2018
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- Authors
- Platzer, K., Cogné, B., Hague, J., Marcelis, C. L., Mitter, D., Oberndorff, K., Park, S., Ploos van Amstel, H. K., Simonic, I., van der Smagt, J. J., Stegmann, A. P. A., Stevens, S. J. C., Stumpel, C. T. R. M., Vincent, M., Lemke, J. R., & Jamra, R.
- Affiliations
- University Hospital Leipzig (DE)
- Centre National de la Recherche Scientifique (FR)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Radboud University Nijmegen (NL)
- Zuyderland Medisch Centrum (NL)
- Department of Genetics Utrecht University Medical Center Utrecht The Netherlands
- Maastricht University Medical Centre (NL)
- Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW) Maastricht University Medical Center Maastricht The Netherlands
- Corresponding author
- Platzer, Konrad
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2018-08
- Volume
- 84
- Issue
- 2
- Pages
- 200-207
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2884074554
- Cited by
- 29
- References
- 30
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 1 · 2020: 1 · 2019: 2
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- CUX1, haploinsufficiency, non-syndromic intellectual disability, global developmental delay, catch-up development, de novo mutations, dendritogenesis, transcription factors
- MeSH terms
- Adult, Child, Developmental Disabilities, Child, Preschool, Female, Humans, Male, Intellectual Disability, Nuclear Proteins, Repressor Proteins, Transcription Factors, Genetic Variation, Homeodomain Proteins, Haploinsufficiency
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