TITLE:
Genomic Analysis of 727 Patients with Ehlers-Danlos Syndrome I: Clinical Perspective Relates 23 Genes to a Maternally Influenced Arthritis-Adrenaline Disorder
AUTHORS:
Golder N. Wilson
KEYWORDS:
Ehlers-Danlos Syndrome, Connective Tissue Dysplasia, Arthritis-Adrenaline Disorder, Articulo-Autonomic Dysplasia, Whole Exome Sequencing, Collagen Genes
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.7 No.12,
December
13,
2019
ABSTRACT: A novel
medical approach for qualifying DNA variants found by whole exome sequencing
(WES) facilitates discovery of new gene-disease relationships and emphasizes
that DNA change must be correlated with clinical findings before having utility
for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process
qualified variants in 23 genes as diagnostically useful in 727 patients having
WES among 1656 with Ehlers-Danlos syndrome (EDS); these results distinguished them from 102 patients who
had qualified gene variants among
728 with developmental disability. Excess maternal transmission of AAD by
pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA
variants and 75 patients with only mitochondrial DNA variants suggest maternal
influence on inheritance of AAD and its subsumed EDS types. Genes grouped by
impact on different connective tissue elements showed variation in similar
numbers of patients with hypermobile or classical EDS, benign joint
hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients; SCN9A/10A/11A, POLG on nerve in 24; COL6A1/A2/A3, COL12 on muscle in 19; COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51; COL3A1, VWF on vessel in 18; COL1A1/A2, COL11A1/A2 acting on
bone in 15 patients. Each gene group acts through a postulated
articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and
dysautonomia findings that transcend EDS types. This same tissue
laxity-dysautonomia cycle acts to produce secondary complications in disorders
ranging from distinctive connective tissue dysplasias to developmental
disorders with hypotonia and acquired conditions with autonomic imbalance.
Several altered genes were previously associated with neuromuscular disorders,
foreshadowing a large myopathic EDS category that will incorporate many
patients with hypermobility. The importance of muscle for joint constraint
supports present exercise and future mesenchymal stem cell therapies, whether
AAD is genetic or epigenetic from trauma, surgery, inflammation, or aging.