Genetic changes across 3 biological systems may drive hypermobile EDS
Study: AI identifies variants linked to immune system, collagen production
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Multiple genetic changes across three major biological systems appear to contribute to hypermobile Ehlers-Danlos syndrome (hEDS), according to a new study that used advanced genetic testing and artificial intelligence (AI).
As in other types of EDS, researchers found changes in genes involved in the production of collagen, a key protein that gives connective tissue its strength and structure. The study also identified changes in genes linked to the immune system and the function of mitochondria, the structures inside cells that produce energy.
“Through systematic clinical [characterization] and genomic analysis of affected families, we have aimed to uncover the genetic architecture underlying hEDS and translate these findings into improved diagnostic and therapeutic strategies,” Michael F. Holick, PhD, MD, a professor at the Boston University Chobanian & Avedisian School of Medicine and the study’s senior author, said in a university news story.
The study, “Multi-System Genetic Architecture of Hypermobile Ehlers–Danlos Syndrome: Integrating Machine Learning with Subject-Level Genomic Analysis,” was published in the journal Genes.
Wide-ranging symptoms make hEDS diagnosis difficult
Very flexible joints, easily bruised tissues, slow or poor wound healing, thin scars, stretchy skin, and scoliosis (abnormal sideways curvature of the spine) are all hallmarks of hEDS.
Beyond these core features, many patients also experience cardiovascular and digestive problems, allergic-type reactions, chronic pain, weak bones, and dizziness or fainting when standing. These wide-ranging symptoms often make diagnosis and treatment difficult.
Because hEDS can run in families, the disease is thought to have a genetic cause. Yet, in most cases, the exact mutations responsible have not been identified. In contrast, mutations in at least 20 different genes are already known to cause other types of EDS, many of which affect collagen production.
“Hypermobile Ehlers-Danlos Syndrome represents [80% to 90%] of all EDS cases, yet the vast majority remain undiagnosed due to lack of awareness among healthcare providers and the absence of a definitive genetic test,” Holick said.
AI analysis finds genetic differences between hEDS patients, controls
To address these gaps, Holick’s team analyzed DNA from 116 people across 43 families, including 86 with hEDS and 30 unaffected family members who served as a control group. They used whole-exome sequencing, which examines the parts of genes that encode proteins, allowing them to study nearly 36,000 rare genetic changes.
To make sense of the large amount of data, the scientists used machine learning, a form of AI that can detect patterns in complex data. Multiple AI methods were combined to improve accuracy and reliability.
The analysis revealed clear genetic differences between people with hEDS and their unaffected relatives, pointing to multiple biological systems rather than a single genetic cause.
The observed HLA gene enrichment in approximately three-quarters of hEDS patients in our cohort suggests a potential role for immune-related genetic variation in disease susceptibility.
As with other types of EDS, many genetic changes occurred in genes involved in collagen production and connective tissue modification, including COL5A1, COL18A1, COL17A1, COL11A1, COL3A1, COL1A2, and PLOD1, PLOD2, and PLOD3. Nearly four times as many people with hEDS carried changes in these genes compared with controls (63% vs. 17%).
“While this observation is consistent with an important but non-universal role for collagen-related genes, these prevalence estimates require validation in independent populations before broader conclusions can be drawn,” the team wrote.
The most common genetic changes were found in immune-related genes, particularly HLA genes, which help the immune system distinguish self from non-self. These included HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DRB1, HLA-DPB1, and TAP1. Here, more than twice as many immune-related variants were found in people with hEDS compared with controls (74% vs. 30%).
“The observed HLA gene enrichment in approximately three-quarters of hEDS patients in our cohort suggests a potential role for immune-related genetic variation in disease susceptibility,” the researchers wrote.
Genetic changes were also identified in genes involved in mitochondrial energy production, including MT-ND5, MT-CYB, MT-ATP8, MT-ND2, MT-ND4, MT-ND6, and MT-ATP6. Nearly five times as many people with hEDS carried these variants compared with controls (33.7% vs. 6.7%).
Among children with hEDS who had a history of fractures, the numbers were even higher compared with those without a fracture history (52% vs. 21%), suggesting “a potential link between energy metabolism and skeletal fragility,” the team noted.
“Our findings identify statistical enrichments across multiple gene categories, such as structural proteins, HLA/immune genes, and mitochondrial genes, generating the hypothesis that hEDS genetic architecture may extend beyond classical collagen pathways,” the researchers wrote.
