Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern

Gärtner, Anna; Burr, Lidia; Klauke, Bärbel; Brodehl, Andreas; Laser, Kai Thorsten; Klingel, Karin; Tiesmeier, Jens; Schulz, Uwe; Knyphausen, Edzard zu; Gummert, Jan; Milting, Hendrik

doi:10.3390/ijms23126685

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…Assessing genetic variants in 89 CMP disease genes yielded one (L)P variant in eight patients, at least one VUS in three patients, and no genetic CMP variant was found in one patient. In the index patient of family #10, the compound heterozygous genotype of two VUS missense variants in fukutin ( FKTN ), inherited in trans from the mother and father, likely explains the clinical phenotype composed of skeletal myopathy and DCM [ 44 ]. From these eight (L)P variants, six were missense and two emerged as stop gain variants.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Seidel

Laser

Klingel³

et al. 2022

JCDD

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Myocarditis is an inflammatory disease of the heart. Pediatric myocarditis with the dilated cardiomyopathy (DCM) phenotype may be caused by likely pathogenic or pathogenic genetic variants [(L)P] in cardiomyopathy (CMP) genes. Systematic analysis of immune disorder gene defects has not been performed so far. We analyzed 12 patients with biopsy-proven myocarditis and the DCM phenotype together with their parents using whole-exome sequencing (WES). The WES data were filtered for rare pathogenic variants in CMP (n = 89) and immune disorder genes (n = 631). Twelve children with a median age of 2.9 (1.0–6.8) years had a mean left ventricular ejection fraction of 28% (22–32%) and myocarditis was confirmed by endomyocardial biopsy. Patients with primary immunodeficiency were excluded from the study. Four patients underwent implantation of a ventricular assist device and subsequent heart transplantation. Genetic analysis of the 12 families revealed an (L)P variant in the CMP gene in 8/12 index patients explaining DCM. Screening of recessive immune disorder genes identified a heterozygous (L)P variant in 3/12 index patients. This study supports the genetic impact of CMP genes for pediatric myocarditis with the DCM phenotype. Piloting the idea that additional immune-related genetic defects promote myocarditis suggests that the presence of heterozygous variants in these genes needs further investigation. Altered cilium function might play an additional role in inducing inflammation in the context of CMP.

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Section: Resultsmentioning

confidence: 99%

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Seidel

Laser

Klingel³

et al. 2022

JCDD

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“…LGMDR9 manifests with a wide clinical variability and evidence suggests that this, in part, reflects the genotype: subjects homozygous for c.826C>A gene variant express a milder phenotype compared to compound heterozygous subjects, but can develop severe cardiomyopathy [71,74]. Cardiomyopathy has also been observed in patients affected by sarcoglycanopathies (LGMDR3-R6) [77][78][79][80][81][82][83][84][85][86][87] and LGMDR13 [88][89][90] in percentages ranging from 12.9 to 50; the tendency to evolution towards dilated cardiomyopathy and heart failure is more frequently observed in patients with EDMD2, LGMDR6, R9, R11, and R13 . Isolated cases of cardiac involvement have also been described in patients with LGMDR7 (defects in telethonin), R10 (defects in titin) [91], and R23 (defects in LAMA 2 gene) [92].…”

Section: Limb-girdle Muscular Dystrophiesmentioning

confidence: 99%

Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review

Politano

2024

IJMS

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Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.

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“…Cardiac symptoms have been more often reported during the second decade of life, especially in patients with subtypes caused by p.Q358P and p.R179T mutations, who experience DCM with minimal muscle weakness [14]. Our systematic search results in 77 patients with FKTN deficiency and cardiac manifestations, encompassing DCM, VD, DI, SI, AF, PFO, double subaortic ventricular defect, HoLV, PPS, MF and infundibular TGA (with no innominate vein) [14,185,[330][331][332][333][334][335][336][337][338][339][340][341][342][343] (Table 5, Supplementary Tables S2 and S3).…”

Section: Fktn-cdgmentioning

confidence: 99%

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Conte,

Sam,

Lefeber

et al. 2023

IJMS

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Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

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Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern

Cited by 4 publications

References 48 publications

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis—Further Impact of Heterozygous Immune Disorder Gene Variants?

Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

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