X-linked FLNA mutation with valvular dysplasia

    Authors

    Keywords

    FLNA mutation, mitral regurgitation, dilatative cardiomyopathy

    DOI

    https://doi.org/10.15836/ccar2025.166

    Full Text

    **Introduction**: FLNA gene codes the protein filamin A that builds the cell cytoskeleton and plays the role in regulating skeletal and brain development, formation of heart tissue and blood vessels, blood clotting, skin elasticity, etc. (1, 2) It is found on the X chromosome and has X linked inheritance. Cardiovascular abnormalities include dilatation and rupture of the thoracic aorta, outflow tract malformations, valvular dysplasia, patent ductus arteriosus (PDA), atrial and ventricular septal defects, etc (3, 4). Individuals diagnosed with FLNA mutation are usually females because this condition is prenatal/neonatal lethal in most males. (3) **Case report**: 19-year-old young man was referred for further follow up due to FLNA mutation (c.4240T>Ap.Tyr1414Asn) and worsening of the left ventricular (LV) function. He was under pediatric cardiologist’s surveillance since birth due to PDA, that was percutaneously closed at the age of 3 years. Regular echocardiography exams revealed myxomatous valves and dilation of the left ventricle. On the CMR dilated LV (EDV 147/ml/m2) with EF of 52% was described, as well as morphological changes of the mitral valve, but no mitral regurgitation (MR). Cardiac CT showed no dilation of the aorta. Genome sequencing was performed and FLNA mutation was found. Afterwards, the same mutation was found in his mother (heterozygotic), whose echocardiogram was normal except mild mitral and tricuspid regurgitation. Our patient was born from mother’s third pregnancy. The first pregnancy ended with a miscarriage, while from the second pregnancy apparently healthy female was born (genetic testing pending). Echocardiography revealed severely dilated left ventricle with reduced ejection fraction (EDV 114ml/m2, LVEF 40%), dilation of the right ventricle (46mm in the apical 4-chamber view) and severe MR (**Figures 1-4**Figure 2Figure 3Figure 4). All heart valves were severely myxomatous with prolapse of the cusps, but with no other significant valvular heart disease. After the new CMR, he will be referred for cardiac surgery. FIGURE 1. Parasternal long axis view in systole (A) and diastole (B) showing prolapse of an extremely myxomatous and thickened anterior mitral leaflet. FIGURE 2. Parasternal biplane short axis views showing an extremely eccentric mitral regurgitation jet. FIGURE 3. Apical 4-chamber view, showing both mitral and tricuspid valve prolapse and pronounced mitral annular disjunction. FIGURE 4. Focused apical 4-chamber view showing the dilated right ventricle and prolapse of the tricuspid valve. **Conclusion**: Spectrum of FLNA mutation phenotype is wide. The most common phenotype in males is valvular dysplasia. Due to complex changes in the structure and morphology of the mitral valve, diagnosis of MR is challenging.

    Literature

    1. Morisaki T, Morisaki H. Genetics of hereditary large vessel diseases. J Hum Genet. 2016 January;61(1):21–6. https://doi.org/10.1038/jhg.2015.119
    2. FLNA gene: MedlinePlus Genetics [Internet]. [cited 2025 Jan 14]. https://medlineplus.gov/genetics/gene/flna/
    3. Chen MH, Walsh CA. FLNA-Related Periventricular Nodular Heterotopia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
    4. Kapur RP, Robertson SP, Hannibal MC, Finn LS, Morgan T, van Kogelenberg M, et al. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with FLNA mutations and x-linked intestinal pseudo-obstruction. Am J Surg Pathol. 2010 October;34(10):1528–43. https://doi.org/10.1097/PAS.0b013e3181f0ae47
    Cardiologia Croatica
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    X-linked FLNA mutation with valvular dysplasia

    Extended Abstract
    Issue5-6
    Published
    Pages166-167
    PDF via DOIhttps://doi.org/10.15836/ccar2025.166
    FLNA mutation
    mitral regurgitation
    dilatative cardiomyopathy

    Authors

    Marija Tomac Stojmenović*ORCIDCounty Hospital for Psychiatry and Rehabilitation Insula, Rab, Croatia
    Irena Ivanac VranešićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Tamara ŽigmanORCIDUniversity Hospital Centre Rijeka, Rijeka, Croatia
    Jadranka Šeparović HanževačkiORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Neven ČačeORCIDUniversity Hospital Centre Rijeka, Rijeka, Croatia
    Vlatka Rešković LukšićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia

    *Correspondence email: marija.tomac.mts@gmail.com

    Full Text

    Introduction: FLNA gene codes the protein filamin A that builds the cell cytoskeleton and plays the role in regulating skeletal and brain development, formation of heart tissue and blood vessels, blood clotting, skin elasticity, etc. (1, 2) It is found on the X chromosome and has X linked inheritance. Cardiovascular abnormalities include dilatation and rupture of the thoracic aorta, outflow tract malformations, valvular dysplasia, patent ductus arteriosus (PDA), atrial and ventricular septal defects, etc (3, 4). Individuals diagnosed with FLNA mutation are usually females because this condition is prenatal/neonatal lethal in most males. (3)

    Case report: 19-year-old young man was referred for further follow up due to FLNA mutation (c.4240T>Ap.Tyr1414Asn) and worsening of the left ventricular (LV) function. He was under pediatric cardiologist’s surveillance since birth due to PDA, that was percutaneously closed at the age of 3 years. Regular echocardiography exams revealed myxomatous valves and dilation of the left ventricle. On the CMR dilated LV (EDV 147/ml/m2) with EF of 52% was described, as well as morphological changes of the mitral valve, but no mitral regurgitation (MR). Cardiac CT showed no dilation of the aorta. Genome sequencing was performed and FLNA mutation was found. Afterwards, the same mutation was found in his mother (heterozygotic), whose echocardiogram was normal except mild mitral and tricuspid regurgitation. Our patient was born from mother’s third pregnancy. The first pregnancy ended with a miscarriage, while from the second pregnancy apparently healthy female was born (genetic testing pending). Echocardiography revealed severely dilated left ventricle with reduced ejection fraction (EDV 114ml/m2, LVEF 40%), dilation of the right ventricle (46mm in the apical 4-chamber view) and severe MR (Figures 1-4Figure 2Figure 3Figure 4). All heart valves were severely myxomatous with prolapse of the cusps, but with no other significant valvular heart disease. After the new CMR, he will be referred for cardiac surgery.

    FIGURE 1. Parasternal long axis view in systole (A) and diastole (B) showing prolapse of an extremely myxomatous and thickened anterior mitral leaflet.

    FIGURE 2. Parasternal biplane short axis views showing an extremely eccentric mitral regurgitation jet.

    FIGURE 3. Apical 4-chamber view, showing both mitral and tricuspid valve prolapse and pronounced mitral annular disjunction.

    FIGURE 4. Focused apical 4-chamber view showing the dilated right ventricle and prolapse of the tricuspid valve.

    Conclusion: Spectrum of FLNA mutation phenotype is wide. The most common phenotype in males is valvular dysplasia. Due to complex changes in the structure and morphology of the mitral valve, diagnosis of MR is challenging.

    Literature

    1. 1.
      Morisaki T, Morisaki H. Genetics of hereditary large vessel diseases. J Hum Genet. 2016 January;61(1):21–6.DOI
    2. 2.
      FLNA gene: MedlinePlus Genetics [Internet]. [cited 2025 Jan 14].Link
    3. 3.
      Chen MH, Walsh CA. FLNA-Related Periventricular Nodular Heterotopia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
    4. 4.
      Kapur RP, Robertson SP, Hannibal MC, Finn LS, Morgan T, van Kogelenberg M, et al. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with FLNA mutations and x-linked intestinal pseudo-obstruction. Am J Surg Pathol. 2010 October;34(10):1528–43.DOI