This study describes a three-generation family with classical Ehlers-Danlos syndrome carrying a rare COL5A1 variant (NM_000093.5(COL5A1):c.4050dup, p.Gly1351fs) that illustrates significant clinical variability within a single family carrying a single pathogenic variant, expanding the phenotypic spectrum associated with this specific variant.
Key Findings
Results
A rare frameshift variant in COL5A1 (NM_000093.5(COL5A1):c.4050dup, p.Gly1351fs) was identified as the causative pathogenic variant segregating across three generations of a family with classical-type Ehlers-Danlos syndrome.
The variant is a duplication resulting in a frameshift: c.4050dup (p.Gly1351fs) in the COL5A1 gene
The variant segregated across three generations of the same family
Classical EDS (cEDS) is caused by pathogenic variants in COL5A1, COL5A2, or COL1A1 genes
The study clarifies and expands the phenotypic spectrum associated with this specific variant
Results
Significant clinical variability was observed among family members carrying the same single pathogenic COL5A1 variant, demonstrating intrafamilial phenotypic polymorphism.
The same rare pathogenic variant produced variable disease expression across three generations
Clinical variability was observed both in terms of phenotypic polymorphism and disease severity within the single family
The case illustrates that a single pathogenic variant can result in a wide spectrum of clinical presentations
EDS is characterized by considerable clinical variability both across EDS subtypes and within individual subtypes
Background
The 2017 International Classification of EDS delineates 13 subtypes caused by pathogenic variants in 19 distinct genes encoding various collagen types or proteins involved in collagen metabolism.
EDS comprises a heterogeneous group of inherited connective tissue disorders
13 subtypes are recognized under the 2017 International Classification
19 distinct genes are implicated across the subtypes
The genes encode various collagen types or proteins involved in collagen metabolism
Results
The study performed a case-based review that expands the known phenotypic spectrum associated with the specific COL5A1 variant c.4050dup (p.Gly1351fs).
Prior literature on this specific variant was clarified and expanded upon
The report is described as a case-based review in addition to the clinical case presentation
The phenotypic spectrum associated with this specific variant is described as being expanded by this report
The family case represents a rare instance of this particular variant being documented across three generations
What This Means
This research describes a family in which three generations of members were affected by classical Ehlers-Danlos syndrome (EDS), a hereditary disorder affecting connective tissue — the material that provides structure and support throughout the body. By analyzing the family's genetic information, researchers identified a single rare mutation in a gene called COL5A1, which provides instructions for making a type of collagen protein. Despite all affected family members carrying the exact same genetic mutation, they displayed notably different symptoms and varying degrees of disease severity, illustrating how one mutation can lead to very different health outcomes even within the same family.
This research suggests that the relationship between a specific gene variant and its physical effects (the 'genotype-phenotype relationship') in classical EDS is complex and not straightforward. The finding that the same mutation can cause widely different clinical presentations challenges the assumption that knowing a person's specific mutation will reliably predict how severely they will be affected. The study also adds new information about what physical features and symptoms can be associated with this particular COL5A1 mutation, expanding scientists' and clinicians' understanding of this rare variant.
For people with EDS and their families, this research highlights the importance of individualized clinical assessment rather than relying solely on genetic test results to predict disease course. It also underscores the value of studying multiple generations within a single family, as this approach can reveal how variable inherited connective tissue disorders can be. The findings contribute to a growing body of knowledge about EDS subtypes and may eventually help improve how patients are counseled about what to expect from their diagnosis.
Akhiiarova K, Loginova E, Kildiyarova R, Khusainova R, Tyurin A. (2026). Clinical Variability of Classical Ehlers-Danlos Syndrome: A Family with Rare COL5A1 Variant and Case-Based Review.. International journal of molecular sciences. https://doi.org/10.3390/ijms27177952