Screening of the
            <i>Filamin C</i>
            Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients

Gómez, Juan; Lorca, Rebeca; Reguero, Julián R.; Morı́s, César; Martı́n, Marı́a; Tranche, Salvador; Alonso, Belén; Iglesias, Sara; Álvarez, Victoria; Díaz‐Molina, Beatriz; Avanzas, Pablo; Coto, Eliécer

doi:10.1161/circgenetics.116.001584

Cited by 73 publications

(76 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…27 Recently FLNC missense variants (but not Ile817Thr) were reported in familial HCM with incomplete penetrance. 28 FLNC was not previously analyzed in this patient. He is a 51-year-old male with no family history of HCM and no personal or family history of neuromuscular abnormalities.…”

Section: Resultsmentioning

confidence: 95%

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Cirino

Lakdawala

McDonough

et al. 2017

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Background As DNA sequencing costs decline, genetic testing options have expanded. Whole exome and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multi-gene panels that have been the cornerstone of genetic testing. Methods and Results Forty-one patients with hypertrophic cardiomyopathy (HCM) who had undergone targeted HCM genetic testing (either multi-gene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants panel genetic testing identified variants classified as pathogenic, likely pathogenic or uncertain significance (VUS). WGS identified 19 of these 20 variants but the variant detection algorithm missed a pathogenic 18-base pair duplication in MYBPC3 due to low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in panel testing: a pathogenic PTPN11 variant and VUSs in ILK and FLNC. WGS also identified 84 secondary findings (mean=2/person, range= 0–6), which mostly defined carrier status for recessive conditions. Conclusions WGS detected nearly all variants identified on panel testing, provided one new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical utility and numerous secondary genetic findings were also identified. While panel testing and WGS provided similar diagnostic yield, WGS offered the advantage of re-analysis over time to incorporate advances in knowledge, but necessitated expertise in genomic interpretation to appropriately incorporate WGS into clinical care.

show abstract

Section: Resultsmentioning

confidence: 95%

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Cirino

Lakdawala

McDonough

et al. 2017

Circ Cardiovasc Genet

View full text Add to dashboard Cite

show abstract

“…One such gene is FLNC , known for a long time exclusively in association with distal and myofibrillar myopathies (Kley et al., ), and only more recently described in connection to cardiac phenotypes (Kley et al., ; Valdes‐Mas et al., ; Vorgerd et al., ). After the first description of FLNC mutation in a familial case of HCM in 2014, the number of reports documenting its role in the development of cardiac disorders has rapidly grown, making FLNC one of the most common genes associated with cardiomyopathies causing about 10% of HCM and up to 5% of DCM (Begay et al., ; Brodehl et al., ; Dal Ferro et al., ; Gomez et al., ; Janin et al., ; Ortiz‐Genga et al., ; Reinstein et al., ; Tucker et al., ; Valdes‐Mas et al., ). Similar to titin , FLNC is linked to all types of cardiomyopathies, including arrhythmogenic cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, RCM myocardial dysfunction, as well as other types of cardiomyopathies, can manifest concomitant with skeletal muscle system pathology, highlighting the involvement of genes expressed both in cardiac and skeletal muscle (Janin et al., ; Konersman et al., ; Kostareva, Sejersen, & Sjoberg, ). One such gene recently associated with several types of cardiomyopathies is FLNC (MIM# 102565) (Begay et al., ; Brodehl et al., ; Gomez et al., ; Ortiz‐Genga et al., ; Reinstein et al., ; Valdes‐Mas et al., ). FLNC encodes filamin C, an actin cross‐linking protein abundant both in cardiomyocytes and skeletal muscle cells.…”

Section: Introductionmentioning

confidence: 99%

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy

et al. 2018

View full text Add to dashboard Cite

Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modeling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig-loop segments often lead to development of RCM. The described FLNC mutations associated with early-onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children.

show abstract

“…None of these reports indicated any observed cardiac phenotype. More recently, the impact of FLNC variation on the heart has been recognized, including reports on dilated cardiomyopathy, 34–36 hypertrophic cardiomyopathy, 37,38 atrial fibrillation, 37,39 and restrictive cardiomyopathy. 9 The phenotypic spectrum associated with FLNC variation is intriguing, suggesting that variants act through divergent and tissue specific manner and/or that variants are modified by other genetic factors present in the given family.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Tucker

McLellan

et al. 2017

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Background Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. Methods and Results We evaluated 8 family members across four generations by history, physical examination, electrocardiography and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (p.V2297M). FLNC encodes Filamin C, a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle, and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of Filamin C localization in cardiac tissue from an affected family member revealed a diminished localization at the z-disk, whereas traditional localization at the intercalated disk was preserved. Stem-cell derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared to controls. Conclusion We have identified a novel variant in FLNC as pathogenic variant for familial RCM, a finding that further expands upon the genetic basis of this rare and morbid cardiomyopathy.

show abstract

Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients

Cited by 73 publications

References 37 publications

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Contact Info

Product

Resources

About