Article ; Online: DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency.
Genetics in medicine : official journal of the American College of Medical Genetics
2022 Volume 25, Issue 1, Page(s) 63–75
Abstract: Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other ... ...
Abstract | Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS. |
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MeSH term(s) | Humans ; DNA Methylation/genetics ; Haploinsufficiency/genetics ; Neurodevelopmental Disorders/genetics ; Genome |
Language | English |
Publishing date | 2022-11-18 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1455352-1 |
ISSN | 1530-0366 ; 1098-3600 |
ISSN (online) | 1530-0366 |
ISSN | 1098-3600 |
DOI | 10.1016/j.gim.2022.10.004 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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