“Sporadic” thoracic aortic aneurysm (taa) in young females may unmask X-linked dominant, type a filaminopathies

Background

Pathogenic variants in Filamin A gene (FLNA, MIM*300017) cause ultra-rare X-linked dominant, phenotypically heterogeneous disorders that may include thoracic aortic aneurysm (TAA). Filamin A is a dimeric actin cross-linking phosphoprotein of the peripheral cytoplasm that links actin filaments to membrane glycoproteins, contributing to cytoskeleton remodeling, cell shape and migration. FLNA-related syndromes include periventricular periventricular nodular heterotopias (PVNH1), X-Linked Cardiac Valvular Dysplasia, Melnick-Needles syndrome, and X-linked congenital idiopathic intestinal pseudo-obstruction, with variable skeletal and haematological features. Females are predominantly affected due to male embryonic lethality. Cardiovascular manifestations include valvular diseases, TAA, and patent ductus arteriosus (PDA). When associated with PVNH1 (MIM#300049), TAA occurs in up to 75% of carriers of FLNA loss-of-function variants (1) frequently observed with bicuspid aortic valve (BAV).

Purpose

We aimed to define and describe the aortic phenotype associated with truncation-predicting FLNA variants in patients presenting with apparently “non-syndromic” TAA.

Methods

Four young female probands diagnosed with TAA before age 30 underwent comprehensive cardiovascular and multidisciplinary evaluation, genetic counselling, NGS multigene panel testing, and whole-body CT angiography. Brain MRI was performed after identification of FLNA variants. Aortic wall samples obtained at surgery underwent histopathological examination and immunostaining for Filamin A expression. Parents underwent clinical and genetic screening.

Results

All probands showed TAA and periventricular heterotopia. None showed bicuspid aortic valve and PDA. Longitudinal monitoring demonstrated slow progression confined to the ascending aorta in three patients and involving both ascending aorta and root in one; dilation progressed faster in the ascending aorta. Two patients reached diameters approaching 50 mm and underwent successful elective valve-sparing aortic repair (Figure 1).

The FLNA defects were classified as pathogenic according to ACMG criteria. All variants are truncation-predicting (PVS1 criterion), absent from population databases (PM2_supporting criterion) and confirmed as de novo (criterion PS2) by family study. (Figure 1). The aortic samples removed at surgery from the two operated patients showed severe structural damage of the aortic wall with elastolysis and massive loss of smooth muscle cells and Filamin A expression (Figure 2).

Conclusion

Female patients with FLNA-related type A filaminopathy, characterised by TAA and periventricular heterotopia,require early diagnosis, structured cardiovascular surveillance, and timely surgery when the aortic diameter approaches 50 mm. Genetic counselling should address the high risk of miscarriage of affected male fetuses due to X-linked dominant inheritance with male embryonic lethality.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.