Introduction: Connective tissue is one of the most important types of tissues in the body, which holds cells together and allows tissues to stretch. Sometimes, for various reasons due to genetic defects, this tissue suffers from various disorders, which are called genetic connective tissue diseases. Genetic or autoimmune connective tissue disease includes a large number of different disorders that can affect the skin, fat, muscle, joints, tendons, ligaments, bone, cartilage, and even the eyes, blood, and blood vessels. the most well-known these disorders are Marfan and related syndromes, Ehlers-Danlos syndrome and Epidermolysis bullosa. In this study, we intend to review the new findings regarding the identification of genes and molecular findings regarding these diseases.
Methods: The electronic databases of MEDLINE, EMBASE, Scopus and other sources were searched for English articles published through January 2020. Three independent reviewers extracted information regarding study design, results and conclusions for each article.
Results: Our review showed that there are not many studies on the identification of genes related to connective tissue disorders and the available findings are very few. The result of examining the findings of the 5 reviewed articles can be summarized as follows:
Studies show a critical role of LH3 in α1α1α2(IV) biosynthesis and suggest that LH3 pathogenic variants might contribute to Gould syndrome.
Study findings suggest that SLC39A13 is included in gene panels designed to address deformity and short stature. This approach may lead to more efficient detection
PLOD genes encode for procollagen lysyl hydroxylase enzymes (LH/PLOD), a family of proteins essential for collagen biosynthesis. Several mutations affect these genes, causing severe disorders, such as Ehlers-Danlos and Bruck syndrome. Mutations in the PLOD1 gene have been linked to kyphoscoliotic Ehlers–Danlos syndrome, and Mutations in the PLOD2 gene have been linked to Bruck syndrome in humans.
The similarity in cEDS and hEDS phenotype in some patients may lead to inaccurate patient classifications.
NGS, with an appropriate multigene panel, showed great potential to assist in the diagnosis of EDS and other connective tissue disorders. NGS provides a platform to analyze a panel of genes known to be related to a specific phenotype in a single test. Through whole-exome sequencing and whole-genome sequencing, it also allows the identification of the responsible mutation(s) in genes not previously associated with the disease. Nevertheless, it is not an absolute method. Using NGS for genomic investigation, we cannot perform some tests, e.g., the null allele test for investigating the well-known mechanism of EDS development. Also, an important drawback of the implementation of next-generation sequencing in genetic diagnostics is the detection of a considerable number of variants of unknown significance (VUSs), especially when analyzing larger gene panels.
Conclusion: Years of investigations showed that Connective tissue disorder are a disorder with a very complex phenotype and highly complicated genotype. The comprehensive mapping of the genetic defects in several connective tissue disorders now allows investigators to address the phenotypic spectrum and natural history of several entities in more detail. This will help to differentiate overlapping phenotypes and redefine confusing clinical classifications. Furthermore, the study of connective tissue disorders has led to many new insights into the assembly and homeostasis of the ECM, including TGFβ signaling, intracellular trafficking, and proper Golgi and mitochondrial functioning.