A mutation update for the FLNC gene in myopathies and cardiomyopathies

• Published in: Human mutation Vol. 41; no. 6; pp. 1091 - 1111
• Main Authors: Verdonschot, Job A. J., Vanhoutte, Els K., Claes, Godelieve R. F., Helderman‐van den Enden, Apollonia T. J. M., Hoeijmakers, Janneke G. J., Hellebrekers, Debby M. E. I., Haan, Amber, Christiaans, Imke, Lekanne Deprez, Ronald H., Boen, Hanne M., Craenenbroeck, Emeline M., Loeys, Bart L., Hoedemaekers, Yvonne M., Marcelis, Carlo, Kempers, Marlies, Brusse, Esther, Waning, Jaap I., Baas, Annette F., Dooijes, Dennis, Asselbergs, Folkert W., Barge‐Schaapveld, Daniela Q. C. M., Koopman, Pieter, Wijngaard, Arthur, Heymans, Stephane R. B., Krapels, Ingrid P. C., Brunner, Han G.
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01-06-2020; John Wiley and Sons Inc
• Subjects: Cardiomyopathy; Dimerization; filamin; FLNC; Genotypes; genotype–phenotype correlation; Haploinsufficiency; Heart; Mutation Update; Myopathy; Phenotypes; Protein folding; Protein structure; filamin; FLNC; cardiomyopathy; myopathy; genotype-phenotype correlation
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.24004

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.
The location of causative variants leading to the filaminopathies A are mapped onto FLNA protein monomers. Variants leading to ‘loss‐of‐function’ disorders (left monomer) and ‘gain‐of‐function’ disorders (right monomer) can clearly be seen to cluster. ‘Hotspot’ regions are marked with larger symbols. PH: periventricular heterotopia, CIPX: congenital intestinal pseudo‐obstruction, IMT: isolated macrothrombocytopenia, FCMPD: familial cardiac myxomatous polyvalvular dystrophy, OPD: otopalatodigital syndrome, FMD: frontometaphyseal dysplasia, CKCO: condition comprising contractures, keloid, cardiac defects and optic anomalies, MNS: Melnick‐Needles syndrome, DCD: digitocutaneous dysplasia, ABD: actin‐binding domain, CHD: calponin homology domain, H: hinge.