16 New COL3A1 Gene Mutations Linked to vEDS in Genetic Testing
Tests ID mutations in largest case series of Asian patients with vEDS
Using genetic testing, researchers in Japan identified 16 new COL3A1 gene mutations associated with vascular Ehlers-Danlos syndrome (vEDS), according to a recent case series.
A range of different types of mutations was identified — each associated with a different level of disease severity and symptoms, or clinical presentation.
“This is the largest case series of Asian patients with vEDS,” the researchers wrote, noting that their screening approach “is useful for the management of vEDS through appropriate differential diagnosis with other clinically overlapping [hereditary connective tissue disorders].”
The team noted that, among other disease factors, “the major criteria include a family history of vEDS with a documented causative variant in COL3A1.”
The study, “Comprehensive genetic screening for vascular Ehlers–Danlos syndrome through an amplification-based next-generation sequencing system,” was published in the American Journal of Medical Genetics Part A.
vEDS is a severe type of Ehlers-Danlos syndrome usually caused by mutations in the COL3A1 gene, which is responsible for producing type III collagen, a structural protein. Because of the potentially serious complications of vEDS, particularly artery ruptures,”accurate diagnosis is critical,” the researchers wrote.
Genetic testing for COL3A1 mutations allows for vEDS to be distinguished from other connective tissue disorders, including other EDS types, that might have overlapping symptoms.
People have two copies of most genes — one inherited from each parent. For COL3A1 , only one of these copies needs to be mutated for vEDS to manifest. This is called dominant inheritance.
A wide range of mutations have been reported to cause vEDS. While they all tend to broadly affect production of sufficient, functional type III collagen, their severity may differ depending on where and how the mutation affects COL3A1.
Now, the researchers — from institutions across the country — reported the results of genetic testing of 429 people seen at Japanese clinics from April 2013 to December 2020. All were suspected of having EDS or another hereditary connective tissue disorder.
Blood samples were collected and genetic testing targeted a panel of genes known to cause connective tissue diseases. For two patients who had died, the analysis was conducted on spleen or liver tissue.
Overall, 1o1 people were suspected to have vEDS based on their clinical presentation. COL3A1 gene mutations were identified in 33 of these people, as well as in two others not initially suspected to have vEDS. The median age at genetic diagnosis for these 35 patients was 32 years.
Among them, 22 had a family history of vEDS-relevant symptoms, and 27 met at least one major criterion for the disease. Of the eight who didn’t, symptoms like lung collapses, and skin and joint problems, were indicative of vEDS.
Ultimately, 18 known COL3A1 mutations and 16 novel ones were identified. Of these 16 newly identified variants, five were considered definitely disease-causing (pathogenic), eight were likely pathogenic, and the remaining three were considered to be of unknown significance.
Most of the identified mutations (20) were missense variants leading to a glycine substitution. This means that a single amino acid — a protein building block — called glycine in the genetic code was switched out for a different amino acid. These mutations are the most common type seen for vEDS, the scientists noted.
But a wide range of other less common mutation types also were reported. Analyses of skin cells from several patients demonstrated that different mutation types led to varying levels of production of type III collagen and alterations to collagen fibers in the skin. Those findings may explain the range of disease severity and differing ages of onset for vEDS patients, the researchers noted.
Some of the mutations found disrupt collagen production only in the mutated copy of the gene, leaving the healthy copy to produce some collagen, though at levels insufficient for normal function; this is called haploinsufficiency.
Other mutations can negatively affect not only the copy of the gene they reside on, but also the protein product of the healthy one — called dominant negative effect. These dominant negative cases are likely to lead to more severe disease, according to the researchers.
For six people in the large group of genetically tested patients who were suspected to have vEDS, mutations were not found in COL3A1, but were identified in other connective tissue disorder genes, namely, TGFBR1, TGFBR2, FBN1, and COL5A1.
“In conclusion, we have presented the details and clinical usefulness of comprehensive genetic screening,” the researchers wrote.
“The system effectively detected a wide spectrum of variants,” they added, noting the cases included both mild and severe disease, as well as atypical presentations.
“Clinical application of this system, and its improvement based on larger numbers of cases, would be required,” the team concluded.