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Verdonschot, J.A.J.; Vanhoutte, E.K.; Claes, G.R.F.; Helderman-van den Enden, A.T.J.M.; Hoeijmakers, J.G.J.; Hellebrekers, D.M.E.I.; ... ; Brunner, H.G. (2020)

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Article / Letter to editor
Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate...Show moreFilamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.Show less
cardiomyopathy
filamin
FLNC
genotype-phenotype correlation
myopathy
All authors
Verdonschot, J.A.J.; Vanhoutte, E.K.; Claes, G.R.F.; Helderman-van den Enden, A.T.J.M.; Hoeijmakers, J.G.J.; Hellebrekers, D.M.E.I.; Haan, A. de; Christiaans, I.; Deprez, R.L.H.; Boen, H.M.; Craenenbroeck, E.M. van; Loeys, B.L.; Hoedemaekers, Y.M.; Marcelis, C.; Kempers, M.; Brusse, E.; Waning, J.I. van; Baas, A.F.; Dooijes, D.; Asselbergs, F.W.; Barge-Schaapveld, D.Q.C.M.; Koopman, P.; Wijngaard, A. van den; Heymans, S.R.B.; Krapels, I.P.C.; Brunner, H.G.
Date
2020-03-20
Journal
Human Mutation: Variation, Informatics and Disease
Volume
41
Issue
6
Pages
1091 - 1111
DOI
doi:10.1002/humu.24004
Link
https://onlinelibrary.wiley.com/doi/10.1002/humu.24004