Connective tissue and aortic disorders

Inheritance varies by gene and subtype. Autosomal dominant inheritance predominates across the syndromic connective tissue disorders and across both syndromic and non-syndromic thoracic aortic disease. Less commonly, thoracic aortic disease is inherited in an X-linked manner (for example, BGN-related disease) or in an autosomal recessive manner (for example, SLC2A10-related disease). De novo pathogenic variants account for a relevant proportion of severe syndromic presentations.

Diagnosis combines clinical evaluation, cardiovascular and ocular imaging, and molecular genetic testing. A heritable disorder is supported by a pathogenic variant in a known gene, by thoracic aortic disease in one or more additional family members, or by aortic disease with features of a recognised syndrome. Multigene panel testing covers the genetic heterogeneity of these overlapping conditions.

Internal differential diagnoses included in this panel:

• : marfanoid habitus with craniosynostosis and skeletal features overlapping Marfan and Loeys-Dietz syndromes; SKI.
• Arterial tortuosity syndrome: tortuosity, elongation and aneurysm of the large and medium arteries, inherited in an autosomal recessive manner; SLC2A10.
• : skin hyperextensibility, atrophic scarring and joint hypermobility, distinct from vascular Ehlers-Danlos syndrome; COL5A1, COL5A2.

External differential diagnoses, non-monogenic:

• Bicuspid aortic valve-associated aortopathy: ascending aortic dilatation linked to the commonest congenital cardiac malformation, predominantly multifactorial rather than monogenic.
• Turner syndrome (45,X): aortic root dilatation and dissection on a chromosomal rather than a single-gene basis warranting karyotype-based assessment.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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