The genetics of hypermobile Ehlers-Danlos syndrome : a local study

Abstract

Background: The Ehlers-Danlos Syndromes (EDS) are a collection of thirteen rare hereditary connective tissue disorders which present with heterogeneous phenotypes. The commonest and less severe subtype, hypermobile Ehlers-Danlos Syndrome (hEDS), presents a vast spectrum of signs and symptoms, including extensive joint hypermobility, musculoskeletal instability, chronic pain and autonomic dysfunction. To date, various international research efforts failed to uncover its molecular genetic aetiology, and this is further confounded by inter-familial genetic heterogeneity. Aims: This original local research study sought to elucidate the genetic aetiology of hEDS in a small group of hEDS patients in Malta and to determine the effect of hEDS on bone mass. Methodology: A multigenerational Maltese family as well as an unrelated participant were recruited. High-throughput sequencing was performed on selected participants using Illumina technology. Genetic analysis was also supplemented with bone mineral density (BMD) scans and testing of serum bone-related analytes. Results: Two research participants had low bone mass and were classified as osteopenic, while serum levels of bone-related analytes were within the physiological range except in one osteopenic participant. Sequencing data was filtered using an in-house filtering pipeline to obtain a list of genetic variants found segregating with the disease phenotype in the family. This yielded five single nucleotide variants, namely TNXB rs61746206 (c.745G>A, p.Glu249Lys), TNXB rs140304758 (c.6973G>A, p.Val2325Ile), SMAD3 rs189286879 (c.206+32287G>A), FANCA/ZNF276 rs201316239 (n.47G>A) and PNPLA1 rs45524833 (c.745G>A, p.Glu249Lys), which were not detected in the un-related participant. These variants were further annotated using gene databases and in-silico prediction tools to determine their clinical relevance. Discussion: None of these variants was found to be pathogenic, thus highlighting the need for further research on larger cohorts and families of hEDS patients. The discovery of a potentially causative genetic pathogenic variation will enable the establishment of an early diagnosis and appropriate clinical management of this multisystemic hereditary disorder.