What is the inheritance pattern of Ehlers-Danlos syndrome (EDS)?

From the Guidelines

Ehlers-Danlos syndrome is primarily inherited in an autosomal dominant pattern, as evident in the vascular form of the disease, which is caused by pathogenic variants in the COL3A1 gene, as stated in the 2024 ESC guidelines 1. This means that a person needs only one copy of the mutated gene from either parent to develop the condition, resulting in a 50% chance of passing the condition to each child. The inheritance pattern can vary depending on the specific type of EDS, with most types following the autosomal dominant pattern, while some rarer forms are inherited in an autosomal recessive manner, requiring two copies of the mutated gene (one from each parent) for the condition to manifest. Some cases of EDS may also occur due to new spontaneous mutations with no family history. Genetic testing can help determine the specific type of EDS and its inheritance pattern, which is valuable for family planning and understanding disease progression, as noted in the context of vascular Ehlers-Danlos syndrome diagnosis requiring identification of a causal COL3A1 variant 1. Key characteristics of vascular Ehlers-Danlos syndrome include:

• A rare autosomal dominant disease with a prevalence of 1/50 000 to 1/200 000
• Caused by pathogenic variants in the COL3A1 gene
• Clinical complications may start during adolescence and repeat at unpredictable time intervals, involving medium-sized arteries, such as dissections, aneurysms, arterial ruptures, and arteriovenous fistulas
• Prognosis depends on the type of COL3A1 variant, with null variants showing a better outcome, and a reduced life expectancy to an average of 51 years, as outlined in the 2024 guidelines 1. In contrast to older guidelines, such as the 2003 expert consensus document on management of cardiovascular diseases during pregnancy 1, the most recent evidence from the 2024 ESC guidelines provides a clearer understanding of the inheritance pattern and genetic causes of Ehlers-Danlos syndrome, particularly the vascular form.

From the Research

Inheritance of Ehlers-Danlos Syndrome

• Ehlers-Danlos syndrome (EDS) is a group of genetic connective tissue disorders that affects approximately 1 in 5,000 live births, including males and females of all racial and ethnic groups 2.
• The main characteristics of EDS are skin hyperextensibility, tissue fragility, and joint hypermobility 2.
• EDS is a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising 3.
• Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types, caused by variants in 20 different genes 3.

Genetic Basis of EDS

• The molecular underpinnings of the hypermobile type of EDS remain unknown 3.
• For the other types of EDS, the molecular cause is related to disturbances of collagen formation and/or stability, caused by pathogenic variants in 21 confirmed genes 4.
• Genetic tests are indicated if clinical features suggest a monogenic EDS type, but are usually unrewarding for other cases of hypermobility 4.
• Skin biopsy with electron microscopy can be helpful in the decision process of whether and when to perform genetic testing 5.

Diagnosis and Management

• Diagnosis of EDS is often difficult due to the complexity of symptoms and lack of specific genetic tests 2.
• Accurate elicitation of history and clinical signs is vital in selecting the correct confirmatory investigation 5.
• Management consists of a care team responsible for surveillance of major and organ-specific complications, integrated physical medicine and rehabilitation 3.
• No specific medical or genetic therapies are available for any type of EDS 3.