Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
Open accessAbstract
Background: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. Methods and results: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. Conclusions: The data do not provide any evidence for phenotype–genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
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EHMT1 haploinsufficiency has been implicated as the cause of 9qSTDS, characterized by moderate-to-severe mental retardation, childhood hypotonia, facial dysmorphisms, and high prevalence of psychiatric symptoms in adulthood.
“EHMT1 haploinsufficieny has been implicated as the cause of the 9q subtelomeric deletion syndrome (9qSTDS) characterised by moderate-to-severe mental retardation, childhood hypotonia and facial dysmorphisms, as well as a high prevalence of psychiatric symptoms in adulthood.31”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [31]
The developmental effects of ehmt mutation on cognition are reversible.
“and potentially point the way to novel therapeutic opportunities as the developmental effects of ehmt mutation on cognition are reversible.31”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [31]
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Self-citation
- Authors
- Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V, Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., Wilson, M., McGaughran, J., Rauch, A., Zenker, M., Adam, M. P., Innes, M., Davies, C., López, A. G.-M., Casalone, R., Weber, A., Brueton, L. A., Navarro, A. D., Bralo, M. P., Venselaar, H., Stegmann, S. P. A., Yntema, H. G., van Bokhoven, H., & Brunner, H. G.
- Affiliations
- Radboud University Medical Center (NL)
- Radboud University Nijmegen (NL)
- Haukeland University Hospital (NO)
- Princess Anne Hospital (GB)
- Sydney Children's Hospital (AU)
- The University of Sydney (AU)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Emory University (US)
- Alberta Children's Hospital (CA)
- Hospital Universitario Virgen del Rocío (ES)
- Ospedale di Circolo e Fondazione Macchi (IT)
- Alder Hey Children's Hospital (GB)
- Birmingham Women's Hospital (GB)
- Hospital Universitario La Paz (ES)
- Corresponding author
- Kleefstra, T
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2009-03-04
- Volume
- 46
- Issue
- 9
- Pages
- 598-606
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2118745131
- Cited by
- 252
- References
- 18
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 12 · 2023: 13 · 2022: 11 · 2021: 13 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 20 · 2016: 16 · 2015: 13 · 2014: 19 · 2013: 15 · 2012: 17
- FWCI
- 16.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.zora.uzh.ch
- Licence
- other-oa
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- EHMT1, haploinsufficiency, premature stop codon, neurodevelopmental disorders, intellectual disability, psychiatric pathology, neurodegeneration, genotype-phenotype correlation, submicroscopic deletions
- MeSH terms
- Abnormalities, Multiple, Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, Chromosomes, Human, Pair 9, Female, Haploidy, Humans, Male, Intellectual Disability, Middle Aged, Molecular Sequence Data, Phenotype, Histone-Lysine N-Methyltransferase, Syndrome, Sequence Alignment, Telomere, Sequence Deletion
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