Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals <i>ACTN2</i> mutation related to hypertrophic/dilated cardiomyopathy and a novel <i>LZTR1</i> variant associated with Noonan syndrome

Kraoua, Lilia; Jaouadi, Hager; Allouche, Mohamed; Achour, Ahlem; Hakim, Kaouthar; Ahmed, Habib Ben; Chaker, Lilia; Mâazoul, Faouzi; Ouarda, Fatma; Zaffran, Stéphane; Mrad, Ridha

doi:10.1002/mgg3.1954

Cited by 10 publications

(7 citation statements)

References 25 publications

(32 reference statements)

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“…The genetic test, as a fundamental investigation for the post-mortem assessment of HCM, was reported in several studies [26,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. The related data obtained from the articles are summarized in Table 2.…”

Section: Molecular Autopsymentioning

confidence: 99%

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review

Cianci,

Forzese,

Sapienza

et al. 2024

IJMS

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Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, and it shows an autosomal dominant pattern of inheritance. HCM can be clinically silent, and sudden unexpected death due to malignant arrhythmias may be the first manifestation. Thus, the HCM diagnosis could be performed at a clinical and judicial autopsy and offer useful findings on morphological features; moreover, it could integrate the knowledge on the genetic aspect of the disease. This review aims to systematically analyze the literature on the main post-mortem investigations and the related findings of HCM to reach a well-characterized and stringent diagnosis; the review was performed using PubMed and Scopus databases. The articles on the post-mortem evaluation of HCM by gross and microscopic evaluation, imaging, and genetic test were selected; a total of 36 studies were included. HCM was described with a wide range of gross findings, and there were cases without morphological alterations. Myocyte hypertrophy, disarray, fibrosis, and small vessel disease were the main histological findings. The post-mortem genetic tests allowed the diagnosis to be reached in cases without morpho-structural abnormalities; clinical and forensic pathologists have a pivotal role in HCM diagnosis; they contribute to a better definition of the disease and also provide data on the genotype–phenotype correlation, which is useful for clinical research.

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Section: Molecular Autopsymentioning

confidence: 99%

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review

Cianci,

Forzese,

Sapienza

et al. 2024

IJMS

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“…Discussion ACTN2 variants are known to cause a wide variety of skeletal muscle and cardiac phenotypes, making their clinical interpretation challenging. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]30 Further, limited functional data is available for most ACTN2 variants, and thus, clinical significance of many variants remains uncertain. 27 Consequently, many variants are still classified as variants of uncertain significance (VUS), according to the American College of Medical Genetics / Association for Molecular Pathology (ACMG/AMP) guidelines.…”

Section: Alpha-actinin-2 Subcellular Localization and Solubilitymentioning

confidence: 99%

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

Ranta-aho,

Felice,

Jonson

et al. 2024

Preprint

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Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene,ACTN2, have been shown to cause distal myopathy.ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. NewACTN2variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations inACTN2-related diseases, actininopathies, persists.ObjectiveThe objective of the study is to characterize the pathomechanisms underlying actininopathies.MethodsFunctional characterization in C2C12 cell models of severalACTN2variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.ResultsThe results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.InterpretationThe results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants inACTN2should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

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“…The early diagnosis of LZTR1 ‐related NS diseases can be challenging, mostly because of their variable expressivity, as well as their nonspecific prenatal presentation. Accordingly, very few adults with LZTR1 ‐related NS affected were reported to date and any of them seemed to be affected by HCM (Kraoua et al, 2022; Sun et al, 2022; Yamamoto et al, 2015).…”

Section: Figurementioning

confidence: 99%

Biallelic LZTR1 variants in a 49‐year‐old woman with hypertrophic cardiomyopathy: A clue for considering LZTR1 in adults

Di Stolfo,

Petracca,

Bevere

et al. 2023

American J of Med Genetics Pt A

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Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome

Cited by 10 publications

References 25 publications

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

Biallelic LZTR1 variants in a 49‐year‐old woman with hypertrophic cardiomyopathy: A clue for considering LZTR1 in adults

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