Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy.
TTN
dilated cardiomyopathy
genotype-phenotype correlation
skeletal myopathy
variant interpretation
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
15
05
2020
revised:
10
07
2020
accepted:
31
07
2020
pubmed:
21
8
2020
medline:
1
6
2021
entrez:
21
8
2020
Statut:
ppublish
Résumé
Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype-phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. Forty-nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A-band. All cardioskeletal probands had onset of proximal-predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Although heterozygous TTNtv in the A-band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb-girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A-band TTNtv who may be at risk for multisystem disease.
Sections du résumé
BACKGROUND
Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized.
METHODS
Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype-phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes.
RESULTS
Forty-nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A-band. All cardioskeletal probands had onset of proximal-predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission.
CONCLUSION
Although heterozygous TTNtv in the A-band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb-girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A-band TTNtv who may be at risk for multisystem disease.
Identifiants
pubmed: 32815318
doi: 10.1002/mgg3.1460
pmc: PMC7549586
doi:
Substances chimiques
Connectin
0
TTN protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1460Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR002733
Pays : United States
Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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