Idiopathic Restrictive Cardiomyopathy Is Primarily a Genetic Disease

Gallego‐Delgado, María; Delgado, Juan; Brossa-Loidi, Vicens; Palomo, Jesús; Marzoa-Rivas, Raquel; Pérez‐Villa, Félix; Salazar-Mendiguchía, Joel; Ruiz-Cano, María J.; González-López, Esther; Padrón-Barthe, Laura; Börnstein, Belén; Alonso‐Pulpón, Luis; García‐Pavía, Pablo

doi:10.1016/j.jacc.2016.04.024

Cited by 61 publications

(42 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, a large subgroup of RCM cases manifesting in childhood have an extremely poor prognosis due to underlying metabolic defects (Lee et al, 2017;Papadopoulou-Legbelou, Gogou, & Evangeliou, 2017;Russo & Webber, 2005). Recent advances in genetic sequencing technology have facilitated the identification of mutations causing early-onset RCM and highlighted the involvement of genes encoding contractile and structural proteins (Gallego-Delgado et al, 2016;Kaski et al, 2008;Kostareva et al, 2016).…”

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

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

show abstract

“…To date, dominant pathogenic variants causing RCM have been reported in DES , ACTC1 , TNNI3 , TNNT2 , TPM1 , MYL3 , MYL , MYPN , TTN , BAG3 , FLNC , TTR , and MYH7 , but the majority of cases are considered idiopathic (Towbin, ). However, recent studies of idiopathic RCM cohorts tested using panels of 100–200 CM‐related genes show some success in identifying additional likely pathogenic variants in genes including: DES , LAMP2 , LMNA , BAG3 , JUP , TTN , and others, with 50%–60% of patients having an identified potentially pathogenic variant (Gallego‐Delgado et al., ; Kostareva et al., ). Although previous reports indicate yields of clinical genetic testing around 20% for RCM (Ackerman et al., ), data are limited.…”

Section: Introductionmentioning

confidence: 99%

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

et al. 2018

View full text Add to dashboard Cite

Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.

show abstract

“…The power and efficiency of WES is demonstrated in the identification of the FLNC mutation in this family, and other pathogenic genes in other RCM pedigrees [8,11,28] , dilated cardiomyopathy [37] , and in disease-gene discovery in general [38] . Although there are commercially available panels to test for mutations in known cardiomyopathy genes, WES is an unbiased search for such mutations and has the power to identify new cardiomyopathy genes.…”

Section: Discussionmentioning

confidence: 92%

“…Typically, these genes encode proteins of the sarcomere, z-disk domain, intermediate filaments, ion channel, intercalated disk, and cytoskeletal proteins [3,[7][8][9][10] . This variable expressivity in cardiomyopathy is seen even within the same family, with multiple diagnoses (including this family and other examples) [7,9,11,12] . RCM can also occur from infiltrative processes, such as amyloid or desmin deposition, often due to genetic mutations.…”

Section: Introductionmentioning

confidence: 79%

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Sanoja¹,

Li²,

Fricker³

et al. 2018

JTGG

View full text Add to dashboard Cite

Aim: Idiopathic cardiomyopathy is often genetic in origin, typically autosomal dominant, and restrictive cardiomyopathy (RCM) is the rarest form. Clinically, RCM prognosis is poor with most patients requiring heart transplant due to impaired diastolic function leading to heart failure. In some cases, desminopathy is also observed, whereby desmin protein aggregates in the myocardium. Many genes are known to be involved in cardiomyopathy, and we sought to find the pathogenic mutation of a four-generation family with RCM and desminopathy. Methods:We employed whole exome sequence analysis of four RCM patients from the family, to identify the underlying pathogenic mutation(s).Results: Analysis of the exome data led to identification of two putative pathogenic variants. One, a nonsense mutation in ADD3, encoding adducin 3, was found in the proband and his affected daughter, but not other family members. The other was a missense mutation (G1546S) in the gene encoding filamin C (FLNC), found in all of the affected individuals. Both of these proteins interact with proteins involved in sarcomere function, and are expressed in both heart and skeletal muscle. FLNC has recently been implicated as a cardiomyopathy gene, but ADD3 has not at this point. Conclusion:We present bioinformatic analyses that suggest that the FLNC variant is the major pathogenic variant affecting this family, but cannot rule out some contribution of the ADD3 mutation in at least two patients.

show abstract

Idiopathic Restrictive Cardiomyopathy Is Primarily a Genetic Disease

Cited by 61 publications

References 5 publications

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

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

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Contact Info

Product

Resources

About