A mutation update for the FLNC gene in myopathies and cardiomyopathies

Job A.J. Verdonschot, Els K. Vanhoutte, Godelieve R.F. Claes, Apollonia T.J.M. Helderman-van den Enden, Janneke G.J. Hoeijmakers, Debby M.E.I. Hellebrekers, Amber de Haan, Imke Christiaans, Ronald H. Lekanne Deprez, Hanne M. Boen, Emeline M. van Craenenbroeck, Bart L. Loeys, Yvonne M. Hoedemaekers, Carlo Marcelis, Marlies Kempers, Esther Brusse, Jaap I. van Waning, Annette F. Baas, Dennis Dooijes, Folkert W. AsselbergsDaniela Q.C.M. Barge-Schaapveld, Pieter Koopman, Arthur van den Wijngaard, Stephane R.B. Heymans, Ingrid P.C. Krapels, Han G. Brunner*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 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.

Original languageEnglish
Pages (from-to)1091-1111
Number of pages21
JournalHuman Mutation
Issue number6
Publication statusPublished - 1 Jun 2020

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© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.


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