Research Update

February 26, 2021

Members of our research community have been asked to provide lay summaries that give a basic overview in clear language of papers about to be published.

The following summary was prepared by Dr. Luigi Boccuto.

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

L. C. Schenkel, E. Aref-Eshghi, K. Rooney, J. Kerkhof, M. A. Levy, H. McConkey, R. C. Rogers, K. Phelan, S. M. Sarasua, L. Jain, R. Pauly, L. Boccuto, B. DuPont, G. Cappuccio, N. Brunetti-Pierri, C. E. Schwartz & B. Sadikovic

Clinical Epigenetics volume 13, Article number: 2 (2021)

This study analyzed the methylation profile of 22 individuals with PMS, 11 with large terminal 22q13 deletions (~2-6 Mb) and 11 with small terminal 22q13 deletions (<1 Mb) or SHANK3 mutations. Methylation of specific sites of the genome is a well-known mechanism of regulation of gene expression, so alterations of the levels of methylation across the genome may affect multiple cellular functions.

The results showed clear differences in the methylation levels between the 2 groups, with the large deletion cases showing a profile clearly distinguishable from the other PMS subgroup, but also from other genetic disorders.

This difference was reflected on metabolic profiles assessed on the same patients: the cases with large deletions showed abnormal responses to a higher number of compounds, indicating more disrupted pathways, probably due to the fact that more genes were affected, both because involved in the 22q13 deletion and both because of the abnormal methylation. One of the possible explanations for these differences is the loss of the BRD1 gene, which maps about 1.5 Mb from the end of the chromosome and is involved in the regulation of genome methylation.

The results of this paper show that individuals with deletions including the BRD1 gene will have abnormal methylation of their genome, resulting in the disruption of several metabolic pathways and higher chances of more severe clinical presentation.

Click here to access the full study.