An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Abstract

SummaryAlthough approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

Down syndrome with co-occurring Marfan syndrome

“…15 There is a possibility of certain genes associated with DS and MFS yielding opposing phenotypes, resulting in compensational or mixed effects. 14 In our patient and others with similar genetic issues, compensational features are observed in cataract, myopia, joint hypermobility and pes planus. On the contrary, dominant expression exists in upslanting versus downslanting palpebral fissure, brachycephaly versus dolichocephaly, short stature versus tall stature and brachydactyly versus arachnodactyly.…”

“… 2 For example, DS has a higher risk of having juvenile myelomonocytic leukaemia comparing to healthy population and this disease is associated with a mutation of the NRAS gene, which is located on chromosome 1. 14 Hence, in DS and MFS co-occurring cases, we think that the dominating specific phenotypic manifestation (such as stature) would be decided by the processes of genetic transcription and genetic translation of that particular gene. On the other hand, gene interplay has been shown between DS and MFS and FBN-1 was found to be upregulated in patients with trisomy of chromosome 21.…”

Big Data for Health

“…For example, this has been used to study different genes on chromosome 21 (HSA21) and their role in Down's Syndrome (DS), as well as to understand the underlying reason why nearly half of DS patients exhibit an overprotection against cardiac abnormalities related to the connective tissue [59]. One hypothesis is based on the recent evidence that there is an overall upregulation of FBN1 in DS (which is normally down regulated in MFS) [59]. The construction of genetic networks will, therefore, provide a clearer picture of how these syndromes are related.…”