Thoracic Aortic Disease in Patients with Heterozygous Variants in FBN2

Background: Inherited thoracic aortic disease defines a group of disorders characterized by aortic aneurysm or dissection and high mortality. The most common genetic causes of thoracic aortic disease are heterozygous pathogenic variants in the FBN1 and ACTA2 genes. Heterozygous FBN2 variants have rarely been associated with aortic disease. Pathogenic variants in the central region (exons 24–35) of FBN2 cause a hereditary connective tissue disorder named congenital contractual arachnodactyly (CCA).

Method: Between January 2016 and April 2021, 398 patients with suspected hereditary connective tissue disorder and/or thoracic aortic disease were clinically characterized in our specialized outpatient clinic for hereditary connective tissue disorders. In this cohort, we analyzed 18 disease genes, as well as 44 disease gene candidates, mostly encoding structural components of the connective tissue, for disease-associated variants by using high-throughput sequencing technology. Obtained sequence variants underwent an in-depth bioinformatics analysis and, if possible and useful, segregation of the variant in family members and/or FBN2 transcript analysis was performed. Variants were classified as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic according to the ACMG-AMP guidelines.

Results: We identified two (likely) pathogenic variants in the FBN2 central region in one family and in one sporadic patient with CCA. Furthermore, we detected a heterozygous variant outside of the central region in FBN2 in eight patients of six families. Four missense variants were classified as variants of uncertain significance, whereas a nonsense and a splice site variant were classified as pathogenic. The splice site variant cosegregated with the disease phenotype in the affected family and resulted in in-frame skipping of exon 43. Two of these eight patients (25%) were diagnosed with CCA and four patients (50%) had thoracic aortic disease without any clinical features of CCA. The remaining two patients (25%) presented with a Marfanoid phenotype without aortic dilatation or dissection.

Conclusion: Our results suggest that autosomal dominantly acting disease-relevant FBN2 variants outside of the central region are associated with thoracic aortic disease rather than CCA. We recommend that (1) FBN2 should be included in the molecular genetic test of patients with aortic disease and (2) patients with likely pathogenic or pathogenic FBN2 variants should undergo aortic imaging.

Publication History

Article published online:
12 February 2022