Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

Ruijmbeek, Claudine W. B.; Housley, Filomena; Idrees, Hafiza; Housley, Michael P.; Pestel, Jenny; Keller, Leonie; Lai, Jason; Linde, Herma C. van der; Willemsen, Rob; Piesker, Janett; Al-Hassnan, Zuhair N.; Almesned, Abdulrahman; Dalinghaus, Michiel; Bersselaar, Lisa M. van den; Slegtenhorst, Marjon A. van; Tessadori, Federico; Bakkers, Jeroen; Ham, Tjakko J. van; Stainier, Didier Y. R.; Verhagen, Judith M.A.; Reischauer, Sven

doi:10.1172/jci.insight.168247

Cited by 2 publications

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“… 65 ) HCM, AF, ECG traits – FLII Actin remodeling protein DCM 2 (refs. 10 , 67 ) 3 3 PTV/missense Exome (3 trio) – Embryonic lethality JPH2 Junctional membrane complex DCM 6 (refs. 7 , 8 , 10 , 68 – 70 ) 7 7 PTV/missense Exome (2 trio, 2 proband).…”

Section: Resultsmentioning

confidence: 99%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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Section: Resultsmentioning

confidence: 99%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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“…Autosomal recessive DCM is due to mutations in a dozen genes which are TNNI3 on chromosome 19q13 (Murphy et al., 2004 ; Sorrentino et al., 2023 ), GATAD1 gene on 7q21 (Theis et al., 2006 ), PPCS gene on 1p34 (Iuso et al., 2018 ), RPL3L gene on 16p13 (Al‐Hassnan et al., 2020 ; Ganapathi et al., 2020 ), JPH2 gene on 20q13 (Jones et al., 2019 ; Vasilescu et al., 2018 ), BAG5 gene on 14q32 (Hakui et al., 2022 ), LMOD2 gene 7q31 (Ahrens‐Nicklas et al., 2019 ; Greenway et al., 2021 ; Yuen et al., 2022 ), GET3 gene on 19p13 (Verhagen et al., 2019 ), CAP2 gene on 6p22 (Aspit et al., 2019 ; Gurunathan et al., 2022 ), and FLII gene on 17p11 (Al‐Hassnan et al., 2020 ; Ruijmbeek et al., 2023 ) causing CMD2A, CMD2B, CMD2C, CMD2D, CMD2I, CMD2F, CMD2I, and CMD2J, respectively. Thus, the main mode of inheritance of pediatric hereditary forms of DCM is autosomal recessive, unlike adult forms which are often autosomal dominant (56%) with variable expressivity and penetrance (Herman et al., 2012 ; McNally & Mestroni, 2017 ; Mestroni et al., 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy

Kraoua,

Louati,

Ahmed

et al. 2024

Molec Gen & Gen Med

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BackgroundDilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.Family descriptionHere, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.ResultsExome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways‐based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.ConclusionGenetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre‐implantation genetic diagnosis possibilities. Our study expands the case series of early‐onset DCM patients with a protein‐truncating variant in the TNNI3 gene by reporting three affected infant siblings.

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Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

Cited by 2 publications

References 62 publications

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy

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