A Novel Nonsense Pathogenic ITTN/I Variant Identified in a Patient with Severe Dilated Cardiomyopathy

• Published in: Current Issues in Molecular Biology Vol. 45; no. 3
• Main Authors: Micolonghi, Caterina, Fabiani, Marco, Pagannone, Erika, Savio, Camilla, Ricci, Marta, Caroselli, Silvia, Gambioli, Vittoria, Musumeci, Beatrice, Germani, Aldo, Tini, Giacomo, Autore, Camillo, Pizzuti, Antonio, Visco, Vincenzo, Rubattu, Speranza, Petrucci, Simona, Piane, Maria
• Format: Journal Article
• Language: English
• Published: MDPI AG 01.03.2023
• Subjects: Cardiomyopathy, Dilated; Ethylenediaminetetraacetic acid; Genetic aspects; Health aspects; Heart; Hypertension; Medical genetics
• ISSN: 1467-3037
• DOI: 10.3390/cimb45030157

Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant acquired risk factors for DCM (hypertension, diabetes, smoking habit, and/or previous alcohol and cocaine abuse) and with a family history of both DCM and sudden cardiac death. The left ventricular systolic function, as assessed by standard echocardiography, was 20%. The genetic analysis performed using TruSight Cardio panel, including 174 genes related to cardiac genetic diseases, revealed a novel nonsense TTN variant (TTN:c.103591A > T, p.Lys34531*), falling within the M-band region of the titin protein. This region is known for its important role in maintaining the structure of the sarcomere and in promoting sarcomerogenesis. The identified variant was classified as likely pathogenic based on ACMG criteria. The current results support the need of genetic analysis in the presence of a family history, even when relevant acquired risk factors for DCM may have contributed to the severity of the disease.