FLNC Mutation Research Articles

75P Evaluation of clinico-pathological and genetic spectrum of FLNC mutations in Indian cohort

75P Evaluation of clinico-pathological and genetic spectrum of FLNC mutations in Indian cohort

Abstract Tu062: FLNC Deficiency Triggers Unfolded Protein Response and Leads to Dilated Cardiomyopathy

Background: The FLNC gene encodes filamin C, which is highly expressed in cardiomyocytes. Dysfunction of filamin C, due to different types of FLNC mutations, has been reported to be associated with various types of cardiomyopathy. Truncating mutations in FLNC often result in insufficient expression of filamin C, resulting in dilated cardiomyopathy (DCM). However, the specific processes via which the deficiency of filamin C causes DCM remain incompletely comprehended. Aims: To investigate the pathogenic mechanisms of DCM caused by the deficiency of filamin C in cardiomyocytes using a mouse model with cardiac-specific knockout of Flnc and to explore potential therapeutic approaches. Methods and Results: We used tamoxifen to induce cardiac-specific Flnc gene knockout in cardiomyocytes and found that mice with cardiac-specific Flnc knockout exhibited left ventricular dilation, heart failure, increased heart weight, cardiomyocyte enlargement and fibrosis, suggesting that Flnc deficiency in cardiomyocytes causes DCM. Transcriptional profiling of primary cardiomyocytes isolated on the seventh day after tamoxifen injections showed the activation of ER stress and the unfolded protein response (UPR) upon Flnc deletion. Then we measured the expression levels of proteins in UPR pathway in cardiac tissue and found that PDI and pIRE1a proteins were significantly upregulated, while there were no changes in the other two branches of UPR, including the PERK and ATF6 branches. Intraperitoneal injection of a PDI inhibitor E64FC26 significantly improved heart function and reduced fibrosis in cardiac-specific Flnc deletion mice. Conclusion: Cardiac-specific knockout of Flnc leads to DCM in mice, during which the UPR pathway is activated. Treatment with the PDI inhibitor E64FC26 improves the heart function and the fibrosis in Flnc -deficient DCM mice, offering novel perspectives on the pathological mechanisms of DCM and providing new insights into therapeutic strategies in treating DCM caused by FLNC dysfunction.

Distribution of myocardial fibrosis in patients with nonischemic cardiomyopathy and ventricular tachycardia based on genetic variant

BackgroundMany genetic nonischemic dilated cardiomyopathies (NICMs) cause ventricular tachycardias (VTs) originating from scar substrate identified as areas of low electrogram voltage. Substrate locations vary, and the causes of scar are not well defined. ObjectiveThis study evaluated VT substrate locations in genetic NICM patients undergoing VT ablation to evaluate spatial relationships between specific variants and substrate locations. MethodsIn this retrospective case series analysis, 32 patients (aged 55 ± 16 years; 94% male; left ventricular ejection fraction, 34% ± 13%) with genetic NICM referred for VT ablation between October 2018 and November 2022 at a single medical center were evaluated. Scar locations were defined as areas of low unipolar or bipolar voltage. ResultsOf the 32 patients evaluated, mutations in TTN (n = 11), LMNA (n = 6), PKP2 (n = 5), MYBPC3 (n = 3), DSP (n = 2), TTR (n = 1), FLNC (n = 1), AGL (n = 1), DES (n = 1), and DSG2 (n = 1) were observed. Substrates associated with mutations in TTN were observed only in basal subregions, predominantly anterior (100%) and septal (50%) regions. LMNA mutations were associated with fibrosis in mid inferolateral (60%) and apical inferolateral (60%) regions. Substrate location for individuals with PKP2 mutations was solely observed in the right ventricle, predominantly basal inferolateral regions. ConclusionUnderstanding spatial relationships between genetic variants causing NICM and VT substrate locations can help lead to generalizable regions in patients with genetically related NICM presenting in VT, which can be investigated during ablation procedures.

Influence of left ventricular ejection fraction, type of mutation and sex on malignant ventricular arrhythmias in dsp and flnc mutations

Abstract Introduction Pathogenic mutations in FLNC and DSP are a common cause of arrhythmogenic left ventricular cardiomyopathy and "arrhythmic dilated cardiomyopathy". We aimed to study demographic and clinical differences amongst these carriers. Purpose 1. To study the prevalence of malignant ventricular arrhythmias in DSP and FLNC mutation carriers in the studies and reports published in the literature. 2. To analyse the effect of age, left ventricular ejection fraction (LVEF), and sex on ventricular arrhythmias in both groups. Methods A systematic review of the human studies published in Medline and EMBASE until September 2022 was carried out. "Desmoplakin Mutations", "Filamin Mutations", "Arrhythmogenic Cardiomyopathy" and "Dilated Cardiomyopathy" were the keywords included in the search queries. Studies, family reports, and registries reporting on individual data of pathogenic or likely pathogenic mutation carriers were selected for analysis. Results Twenty-four articles published between 2002 and 2020 were selected from a total of 430 entries. 171 DSP carriers (from 16 studies) and 169 FLNC carriers (from 7 studies) were included in the analysis. Mean age was similar in both groups: 39.45±19.23 years in DSP vs 42.02±16.27 in the FLNC group (p:0.201). The proportion of females was higher among DSP carriers than that found among FLNC carriers: 101 (59%) vs 76 (45%), p: 0.012. Non-missense mutations were more frequent in both groups: 98 DSP carriers (57%) and 157 FLNC carriers (97%). LVEF was slightly more depressed amongst FLNC carriers: 47.75±14.94% vs 52.37±14.64%, p:0.014. A total of 81 major arrhythmic events (sudden death, ventricular fibrillation, sustained ventricular tachycardia were reported. The LVEF of the male patients that had suffered a major event was similar in both groups (39.13±18.20% in DSP vs 39.03±12.24% in FLNC, p:0.987). On the contrary, LVEF was significantly lower in female carriers of DSP mutations (32.33±15.65% in DSP vs 47.60±15.88% in FLNC, p:0.050). Male carriers show a worse prognosis than their female counterparts (log-rank 0.005) (Figure). The difference was not significant after adjusting for LVEF and type of mutation (missense vs non-missense). LVEF (HR 0.94 per percentage unit (0.91-0.96), p <0.001) and non-missense mutations (HR 0.21 (0.07-0.66), p:0.008) were inversely associated with adverse outcomes in DSP carriers in a multivariate analysis. LVEF was also associated with a better outcome in FLNC carriers (HR 0.97 (0.95-0.99), p: 0.019. Conclusion Moderate systolic dysfunction is a risk factor for malignant arrhythmias amongst DSP and FLNC mutation carriers. Female FLNC carriers with mild systolic dysfunction are at risk for sustained ventricular arrhythmias. Missense DSP mutations are associated with poor arrhythmic prognosis.Sex differences in survival

Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients carrying heterozygous FLNC mutations

Dilated cardiomyopathy (DCM) is a heterogeneous cardiac disorder characterized by left ventricular dilatation and dysfunction. Mutations in dozens of cardiac genes have been connected to the development of DCM including the filamin C gene (FLNC). We generated two induced pluripotent stem cell (iPSCs) lines from DCM patients carrying single missense heterozygote FLNC mutations (c.6689G > A and c.3745G > A). Both lines expressed high levels of pluripotency markers, differentiated into derivatives of the three germ layers and possessed normal karyotypes. The derived iPSC lines can serve as powerful tools to model DCM in vitro and as a platform for therapeutic development.

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

BackgroundFLNC is one of the few genes associated with all types of cardiomyopathies, but it also underlies neuromuscular phenotype. The combination of concomitant neuromuscular and cardiac involvement is not often observed in filaminopathies and the impact of this on the disease prognosis has hitherto not been analyzed.ResultsHere we provide a detailed clinical, genetic, and structural prediction analysis of distinct FLNC-associated phenotypes based on twelve pediatric cases. They include early-onset restrictive cardiomyopathy (RCM) in association with congenital myopathy. In all patients the initial diagnosis was established during the first year of life and in five out of twelve (41.7%) patients the first symptoms were observed at birth. RCM was present in all patients, often in combination with septal defects. No ventricular arrhythmias were noted in any of the patients presented here. Myopathy was confirmed by neurological examination, electromyography, and morphological studies. Arthrogryposes was diagnosed in six patients and remained clinically meaningful with increasing age in three of them. One patient underwent successful heart transplantation at the age of 18 years and two patients are currently included in the waiting list for heart transplantation. Two died due to congestive heart failure. One patient had ICD instally as primary prevention of SCD. In ten out of twelve patients the disease was associated with missense variants and only in two cases loss of function variants were detected. In half of the described cases, an amino acid substitution A1186V, altering the structure of IgFLNc10, was found.ConclusionsThe present description of twelve cases of early-onset restrictive cardiomyopathy with congenital myopathy and FLNC mutation, underlines a distinct unique phenotype that can be suggested as a separate clinical form of filaminopathies. Amino acid substitution A1186V, which was observed in half of the cases, defines a mutational hotspot for the reported combination of myopathy and cardiomyopathy. Several independent molecular mechanisms of FLNC mutations linked to filamin structure and function can explain the broad spectrum of FLNC-associated phenotypes. Early disease presentation and unfavorable prognosis of heart failure demanding heart transplantation make awareness of this clinical form of filaminopathy of great clinical importance.

Drosophila CRISPR/Cas9 mutants as tools to analyse cardiac filamin function and pathogenicity of human FLNC variants.

ABSTRACTFilamins are large proteins with actin-binding properties. Mutations in FLNC, one of the three filamin genes in humans, have recently been implicated in dominant cardiomyopathies, but the underlying mechanisms are not well understood. Here, we aimed to use Drosophila melanogaster as a new in vivo model to study these diseases. First, we show that adult-specific cardiac RNAi-induced depletion of Drosophila Filamin (dFil) induced cardiac dilatation, impaired systolic function and sarcomeric alterations, highlighting its requirement for cardiac function and maintenance of sarcomere integrity in the adult stage. Next, we introduced in the cheerio gene, using CRISPR/Cas9 gene editing, three missense variants, previously identified in patients with hypertrophic cardiomyopathy. Flies carrying these variants did not exhibit cardiac defects or increased propensity to form filamin aggregates, arguing against their pathogenicity. Finally, we show that deletions of the C-term part of dFil carrying the last four Ig-like domains are dispensable for cardiac function. Collectively, these results highlight the relevance of this model to explore the cardiac function of filamins and increase our understanding of physio-pathological mechanisms involved in FLNC-related cardiomyopathies.

Clinical Exome Sequencing Revealed a De Novo FLNC Mutation in a Child with Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium caused by mutations in several genes including TNNT2, DES, TNNI3, MYPN and FLNC. Individuals affected by RCM often develop heart failure at a young age, requiring early heart transplantation. A 7-year-old patient was referred for genetic testing following a diagnosis of restrictive cardiomyopathy. Clinical exome sequencing analysis identified a likely pathogenic mutation in the FLNC gene [(NM_001458.5 c.6527_6547dup p.(Arg2176_2182dup)]. Its clinical relevance was augmented by the fact that this variant was absent in the parents and was thus interpreted as de novo. Genetic testing is a powerful tool to clarify the diagnosis, guide intervention strategies and enable cascade testing in patients with pediatric-onset RCM.

Function alteration of engineered heart tissues carrying a shorter filamin C protein induced by CRISPR/Cas9

Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and systolic dysfunction beginning in young adults and leading to heart failure with few treatment options. Loss-of-function mutations in the FLNC gene, encoding Filamin C, including splicing mutations, have been strongly associated with an arrhythmogenic DMC phenotype. FLNC-related cardiomyopathies are autosomal dominant disease and the mechanisms leading to the phenotype are not fully understood. In vitro models are needed to improve knowledge of pathogenic mechanisms. A control iPSc line (ICAN-403.3) was established from healthy donor fibroblasts and a mutated FLNC subclone (ICAN-FLNC-42.1) was derived using CRISPR/Cas9 technology. The iPSc cells were then differentiated into cardiomyocytes and beating pseudo-tissues in order to study the functional effects of the mutation. We generated two iPS clones, one derived from the other after mutation induced by non-homologous CRISPR/Cas9-dependent DNA repair. The clones were characterized for their pluripotency (immunoflurescence and qPCR of genes expressed in the pluripotent state, alkaline phosphatase test), their genomic integrity (exome, karyotype) and for their capacity for differentiation in the 3 layers (ScoreCard). More specifically, these cells can be differentiated into beating cardiomyocytes (> 85% of cells express troponin T) and exhibit sarcomeric striation by immunostaining of actinin-2. Sequencing shows that the mutation induced by CRISPR/Cas9 is a deletion of the 3′ terminal of exon 42 of the FLNC gene found in the homozygous state [Chr7(GRCh38):g.128854898_128854915del] and lead to the deletion of the consensus donor splice site of exon 42. Additionally, no off-target in cardiac expressed genes has been detected by exome sequencing. Analysis by RT-PCR and immunoblot shows that the mutation induces a exon 42 skipping and reduced expression of a protein of lower molecular weight. Cardiac tissues records for 3 weeks [engineered heart tissue (EHT) generated from the two iPS clones differentiated into cardiomyocytes] show, for the mutant, a lower beat frequency and a higher arrhythmia index. This model will make it possible to understand the pathophysiological mechanism of DCM due to FLNC mutations. These models are also useful for testing potential therapeutic pathways.

Generation of CRISPR-Cas9 edited human induced pluripotent stem cell line carrying FLNC exon skipping variant.

Loss-of-function (LoF) mutations in FLNC are strongly associated with dilated cardiomyopathy (DCM). Using CRISPR/Cas9 mediated edition in an healthy donor derived iPSC (ICAN-403.3) we subcloned 1 iPSC line harboring LoF mutation in FLNC. All lines are fully pluripotent and isogenic except at edited site where it presents a homozygous (ICAN-FLNC42.1) deletion of splice site leading to skipping of exon 42 traduced into a short filamin form with reduced expression in derived cardiomyocytes. This line would serve for FLNC mutation DCM modeling after differentiation into cardiocytes or beating organoids.

A CRISPR/Cas9 strategy for the generation of a FLNC knockout hESC line (WAe009-A-70) to model dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy

The FLNC gene encodes the sarcomeric protein filamin C which plays a central role in cardiomyocytes. Truncating FLNC mutations (stop or frameshift etc.) also cause dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). To further understand the exact role of FLNC in DCM, we have generated a human FLNC knockout cell line from the original embryonic stem cell line H9 by CRISPR/Cas9 gene editing technology in this study. The establishment cell line WAe009-A-70 have a compound heterozygous 4 bp deletion/13 bp deletion in the exon 1 of FLNC which resulted in a frameshift in the translation of FLNC. No filamin C protein was detected in cardiomyocytes differentiated from this cell line. Moreover, WAe009-A-70 also expressed pluripotency markers, maintained the ability to differentiate into the three germ layers in vitro and had a normal karyotype.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

FLNC-Associated Myofibrillar Myopathy: New Clinical, Functional, and Proteomic Data.

ObjectiveTo determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).MethodsWe performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the FLNC mutation were investigated with interaction and transfection studies and biophysics molecular analysis.ResultsEight patients revealed clinical features of slowly progressive proximal weakness associated with a heterozygous c.8025_8030delCAAGACinsA (p.K2676Pfs*3) mutation in FLNC. Two patients exhibited a mild cardiomyopathy. MRI of skeletal muscle revealed lipomatous changes typical for MFM with FLNC mutations. Muscle biopsies showed characteristic MFM findings with protein aggregation and lesion formation. The proteomic profile of aggregates was specific for MFM-filaminopathy and indicated activation of the ubiquitin-proteasome system (UPS) and autophagic pathways. Functional studies revealed that mutant FLNc is misfolded, unstable, and incapable of forming homodimers and heterodimers with wild-type FLNc.ConclusionsThis new MFM-filaminopathy family confirms that expression of mutant FLNC leads to an adult-onset muscle phenotype with intracellular protein accumulation. Mutant FLNc protein is biochemically compromised and leads to dysregulation of protein quality control mechanisms. Proteomic analysis of MFM protein aggregates is a potent method to identify disease-relevant proteins, differentiate MFM subtypes, evaluate the relevance of gene variants, and identify novel MFM candidate genes.

Camptocormia with novel FLNC mutation: A Case Report (114)

Camptocormia with novel FLNC mutation: A Case Report (114)

Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy.

Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from “bench to bedside” can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel “personalized” therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases.

Filmin-c mutations in arrhythmogenic cardiomyopathy: a peculiar association with left dominat variant and high risk of sudden death

Abstract Introduction Arrhythmogenic cardiomyopathy (AC) is characterized by myocyte necrosis and progressive fibro-fatty substitution. Recently, truncated mutations on Filamin C gene have been correlated with AC and a peculiar phenotype characterized by a prominent left ventricular fibrosis and high risk of sudden death. Purpose To evaluate clinical and instrumental features of subjects affected by AC in whom genetic study identified presence of truncating and missense mutations on FLNC gene. Materials and methods A population of 192 probands affected by AC according to 2010 Task Force Criteria or McKenna's proposed criteria for left dominant AC were evaluated for FLNC variants. In positive probands and families anamnestic and clinical data (ECG, echocardiographic and cardiac magnetic resonance (CMR), twenty-four-hours ECG monitoring) were evaluated. Results A total of 19 subjects (9 probands and 10 family members) were identified as carrier of nine different FLNC mutations (5 truncating and 4 missense). In 3 patients (23%) clinical onset was characterized by major arrhythmic episodes and in one (8%) by sudden death. In 6 (46%) ECG was unremarkable and the most common abnormalities were low QRS voltages in peripheral leads (85%), followed by T wave inversion in lateral (15%) and in inferior leads (16%). Twenty-four-hours ECG monitoring revealed a high arrhythmic burden (PVC >500/die) in 6 cases (46%). CMR was performed in all patients. Four of them (31%) showed a LV dilatation, while in 2 cases (15%) a RV dilatation was present. In 8 (61%) a fatty infiltration was detected mainly affecting the left ventricle (6 cases, 46%). Moreover, late enhancement was present in 8 cases (62%), with a LV distribution. Conclusions This is the first studied population in which both truncating and missense variants were evaluated as causative of AC, confirming that FLNC gene mutations are rare (4% of probands without known AC causative mutations) and the prevalent clinical expression is a left dominant phenotype with a high degree of electrical instability and recurrence of sudden familial cardiac death. Funding Acknowledgement Type of funding source: None

Abstract 454: Modeling FLNC Mutations Causing Cardiomyopathy

Genetic mutations lead to cardiomyopathy, a condition linked to heart failure and arrhythmias.Mutations in the FLNC gene have recently been reported in multiple forms of cardiomyopathyincluding dilated, hypertrophic and restrictive forms. The FLNC gene encodes filamin C, anactin-binding protein highly expressed in the heart and skeletal muscle. Filamin C is comprisedof three domains: an actin-binding domain at the N-terminus, a rod domain consisting of 24 Igrepeats in the mid region, and a dimerization domain at the C-terminus. Missense mutations in FLNC have also been described in myofibrillar myopathy, a disorder in skeletal musclecharacterized by intracellular aggregates within muscle. Where examined, FLNC mutant heartsdo not have evident protein aggregation leading to the hypothesis that FLNC mutations havedifferent modes of action in skeletal and cardiac muscle. We identified a FLNC Val2715fs87Xmutation in a 55 yo M with cardiac fibrosis and a history of arrhythmias. We found a second FLNC mutation, Glu2458SerfsX71, which was found in a family with sudden death andhypertrophic cardiomyopathy. A third FLNC mutation, Arg650X, was found in a 41 yo F withhistory of postpartum cardiomyopathy; this patient also harbors a second FLNC variant ofuncertain significance, intron 5, c.970-4A>G (Intronic), which is predicted to affect splicing onher other FLNC allele. Notably, this patient was diagnosed with a muscle disorder in early life.Finally, a fourth FLNC variant, Phe106Leu, found in two brothers with skeletal and cardiacmyopathy was also studied. To examine the mechanisms by which FLNC mutations causecardiomyopathy, we generated patient-derived induced pluripotent stem cells (iPSCs) anddifferentiated these cell lines into cardiomyocytes. Cardiomyocyte function was analyzed usingautomated field potential measurements with the Nanion CardioExcyte. We identified a slowerrate of repolarization with FLNC truncations compared to control. These data demonstrate thepathogenic findings associated with FLNC mutations and provide mechanistic insight intocardiomyopathy and arrhythmias resulting from these mutations.

Myopathies with finger flexor weakness: Not only inclusion-body myositis.

Muscle disorders are characterized by differential involvement of various muscle groups. Among these, weakness predominantly affecting finger flexors is an uncommon pattern, most frequently found in sporadic inclusion-body myositis. This finding is particularly significant when the full range of histopathological findings of inclusion-body myositis is not found on muscle biopsy. Prominent finger flexor weakness, however, is also observed in other myopathies. It occurs commonly in myotonic dystrophy types 1 and 2. In addition, individual reports and small case series have documented finger flexor weakness in sarcoid and amyloid myopathy, and in inherited myopathies caused by ACTA1, CRYAB, DMD, DYSF, FLNC, GAA, GNE, HNRNPDL, LAMA2, MYH7, and VCP mutations. Therefore, the finding of finger flexor weakness requires consideration of clinical, myopathological, genetic, electrodiagnostic, and sometimes muscle imaging findings to establish a diagnosis.

Clinical exome sequencing revealed that FLNC variants contribute to the early diagnosis of cardiomyopathies in infant patients.

FLNC encodes actin-binding protein and is mainly concentrated in skeletal and cardiac muscle. Mutations in FLNC were found in cardiomyopathies. To date, studies on FLNC-cardiomyopathies have mainly been reported in adults. There are limited studies that have investigated FLNC variants in pediatric patients with cardiomyopathies. We summarized the patients who carried rare variants of FLNC from May 2016 to May 2019 in the Center for Molecular Medicine, Children's Hospital of Fudan University, from clinical exome sequencing data. A total of 5 patients with FLNC rare variants were included. Of them, 3 were male and 2 were female. The median age was 3 months (range from 19 days to 30 months). A1186V was a known pathogenic variant reported in pediatric patients with cardiomyopathy (PMID: 29858533), and the other four variants were novel. In the four novel variants, there are one splicing (c.2265+4del) and three missense (p.R441I, p.C1639Y, and p.A2648S). Two patients (patients 1 and 3) were diagnosed with restrictive cardiomyopathy, two patients (patients 2 and 5) were diagnosed with dilated cardiomyopathy, and one patient (patient 4) was diagnosed with arrhythmia. All five patients have survived to date. In summary, FLNC rare variants identified by clinical exome sequencing provide genetic evidence to make early diagnosis of cardiomyopathy in infant patients.

P.82First clinical and neuropathological description of a myofibrillar myopathy with congenital onset based on a homozygous recessive FLNC mutation

Filamin C encoded by the FLNC gene is a large actin-cross-linking protein involved in reorganization of actin cytoskeleton in response to signaling events and displaying structural functions at the Z-lines in muscle cells. FLNC-related disorders have been associated with myofibrillar myopathies of adult onset and dominant inheritance. Here, we describe the case of a boy of a consanguineous family with a congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development without cardiac involvement. We performed molecular genetic testing, histopathologic and morphological analyses (including electron microscopy), analysis of the proteomic signature and a FLNC folding assay. Two homozygous mutations (chr7:128478771 C>G; c.1325C>G; homozygous p.Pro442Arg in exon 8) in the FLNC-rod domain were found. The pathogenicity of these mutations could be confirmed by functional analysis. The heterozygous parents are clinically healthy. Based on the mode of inheritance and clinical details, we - for the first time - identified a patient with congenital autosomal recessive myopathy due to a homozygous variant in the FLNC. The disease course started in the neonatal period as a congenital myopathy with development of a distal myopathy in childhood without cardiac involvement, so far. Thus, our combined findings extend the currently recognized clinical and genetic spectrum of filaminopathies.