Ehlers-Danlos Syndromes (EDS) encompass a diverse group of inherited disorders affecting connective tissue, which provides structural support for skin, tendons, ligaments, blood vessels, and internal organs. Impairment of this tissue leads to the characteristic features of the syndromes. Since EDS is a genetic condition, families often ask how it is passed down and whether a parent must display symptoms for a child to be affected. Understanding the varied inheritance patterns is necessary to address the common query of whether EDS can truly skip a generation.
The Genetic Basis of Ehlers-Danlos Syndromes
EDS arises from pathogenic variants (mutations) in genes that instruct the production or processing of connective tissue proteins. The most affected protein is collagen, which provides strength and structure to tissues. For example, classical EDS (cEDS) is often caused by mutations in the COL5A1 or COL5A2 genes, while vascular EDS (vEDS) involves the COL3A1 gene, which affects Type III collagen and supports blood vessel walls.
Currently, 13 distinct types of EDS are recognized, and 12 have an identified genetic cause. Hypermobile EDS (hEDS), the most common type, remains a clinical diagnosis because its specific genetic cause has not yet been definitively identified. These genetic changes disrupt the structural integrity of the extracellular matrix, leading to the joint hypermobility, skin hyperextensibility, and tissue fragility seen across the syndromes.
Modes of Inheritance for EDS
The inheritance of EDS depends on its specific pattern, typically Autosomal Dominant or Autosomal Recessive. In Autosomal Dominant inheritance, a person needs only one copy of the pathogenic gene variant from either parent to have the condition. Classical, vascular, and hypermobile EDS follow this pattern. An affected parent has a 50% chance of passing the condition to each child, regardless of sex, as the variant is located on a non-sex chromosome.
Autosomal Recessive inheritance is less common and requires a person to inherit two copies of the pathogenic variant, one from each parent, to be affected. Parents of a child with a recessive condition are usually asymptomatic carriers, possessing one copy of the variant without having the syndrome themselves.
If a carrier has a child with another carrier, the syndrome may suddenly appear in the child, giving the appearance of having skipped the parents’ generation. The condition did not truly skip a generation but was instead silently carried by asymptomatic parents who were clinically healthy.
Why EDS Appears to Skip a Generation
The primary reason EDS appears to skip a generation, especially for dominant forms, is incomplete penetrance. Penetrance describes the likelihood that a person who inherits a gene variant will actually exhibit signs and symptoms of the condition. Incomplete penetrance means a person may inherit the disease-causing variant but show no clinical signs of EDS, making it seem as though the gene passed over them entirely.
Variable expressivity further complicates the visible inheritance pattern. This means individuals who inherit the same gene variant can display a wide range of symptoms, from very mild to severe. A parent with a minimally expressed version of EDS might be misdiagnosed or considered unaffected. If their child has a much more severe and noticeable form, it appears the syndrome has reappeared unexpectedly in the next generation.
In some cases, a person is the first in their family to have EDS due to a de novo mutation. This is a new genetic variant that arose spontaneously in the egg, sperm, or early development of the child. A de novo mutation means the condition was not inherited from either parent and represents a new genetic beginning, not a skipped generation.
Genetic Counseling and Testing for Families
Families with a history of EDS should consult with a genetic counselor for an accurate interpretation of their risk and inheritance patterns. Counselors are trained professionals who analyze family medical histories and explain the complexities of inheritance, helping families understand the probability of a child inheriting the condition based on the specific EDS type.
Genetic testing is available for 12 of the 13 types of EDS, allowing for a definitive molecular diagnosis by identifying the causative gene variant. This testing confirms the presence of the variant, even in individuals with incomplete penetrance, and is particularly helpful for family planning. Genetic testing for non-hEDS types can also inform options like preimplantation genetic diagnosis (PGD).
Since the genetic cause of hypermobile EDS (hEDS) is unknown, its diagnosis remains clinical, and genetic testing cannot confirm its presence. However, testing can be used to rule out other types of EDS or connective tissue disorders that present with similar symptoms. Genetic counseling provides individualized risk assessment and facilitates informed decisions about family planning and medical management.