Exploring the Familial Phenotypic Variability Associated With <scp>TTN</scp> Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype–Phenotype Correlation and Consequences in Genetic Counseling

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.

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Publication Details

Journal
Clinical Genetics
Published
2025-01-22
DOI
https://doi.org/10.1111/cge.14679
Citations
1
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
1.39
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article

Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype–Phenotype Correlation and Consequences in Genetic Counseling

Caroline Rooryck, Pascal de Groote, Philippe Charron, Flavie Ader et al.
1 citations
Clinical Genetics
Cardiomyopathy and Myosin Studies
1.39
article

Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype–Phenotype Correlation and Consequences in Genetic Counseling

Caroline Rooryck, Pascal de Groote, Philippe Charron, Flavie Ader, Yann Troadec, Erwan Donal, Christine Coubes, Anne‐Claire Bréhin, Isabelle Magnin‐Poull, Marie Massier, Pascale Richard, Julie Proukhnitzky, Xavier Le Guillou Horn, Patricia Réant, Estelle Gandjbakhch
article en
1 citations

Abstract

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.

Clinical GeneticsVol. 107(4)
Inserm (FR), Université Paris Cité (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Lille’s Cardiology Hospital (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Centre Hospitalier Universitaire de Reims (FR), Centre Hospitalier Universitaire de Poitiers (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Centre Hospitalier Universitaire de Rouen (FR), Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR), Centre Hospitalier Universitaire de Rennes (FR), Université de Rouen Normandie (FR), Université de Reims Champagne-Ardenne (FR), Université de Caen Normandie (FR)
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Cardiomyopathy and Myosin Studies
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