American journal of clinical pathology · 2025
Follow the LINE: A novel case of dilated cardiomyopathy caused by a LINE-1 insertion in the TTN gene.
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Ding Qiliang, Fine Jenna, Hoffman Frank T, Kluge Michelle L, Kuennen Rhonda K, Thieke Sarah M, Hoppman Nicole L, Marcou Cherisse A, Rowsey Ross A, Thorland Erik C, Baudhuin Linnea M, Moyer Ann M, Buglioni Alessia
Аннотация
OBJECTIVES: Protein-truncating variants in the TTN gene are a well-established cause of dilated cardiomyopathy (DCM). We report a novel case of DCM caused by a mobile element insertion (MEI) in TTN, through which we highlight the key features of MEIs in next-generation sequencing data. Because of the rarity of MEIs, the next-generation sequencing data features associated with these events may be mistaken as noise, potentially leading to missed diagnoses.
METHODS: Next-generation sequencing gene panel testing for DCM was performed on a 17-year-old male patient presenting with severe left ventricular dilatation and systolic dysfunction. Manta was used for structural variant detection, followed by manual review of NGS data for potential structural variants.
RESULTS: Manta detected a potential insertion in TTN. Manual review identified hallmark features consistent with a LINE-1 MEI. This finding was orthogonally confirmed by long-range polymerase chain reaction and gel electrophoresis, which indicated an insertion of approximately 4 to 5 kilobase pairs. The insertion disrupted the reading frame of TTN within an A-band exon, resulting in protein truncation that was classified as likely pathogenic.
CONCLUSIONS: This case expands the mutational spectrum of TTN protein-truncating variants. It also underscores the importance of recognizing rarer types of pathogenic variants (eg, MEIs) to produce accurate genetic diagnostics.
METHODS: Next-generation sequencing gene panel testing for DCM was performed on a 17-year-old male patient presenting with severe left ventricular dilatation and systolic dysfunction. Manta was used for structural variant detection, followed by manual review of NGS data for potential structural variants.
RESULTS: Manta detected a potential insertion in TTN. Manual review identified hallmark features consistent with a LINE-1 MEI. This finding was orthogonally confirmed by long-range polymerase chain reaction and gel electrophoresis, which indicated an insertion of approximately 4 to 5 kilobase pairs. The insertion disrupted the reading frame of TTN within an A-band exon, resulting in protein truncation that was classified as likely pathogenic.
CONCLUSIONS: This case expands the mutational spectrum of TTN protein-truncating variants. It also underscores the importance of recognizing rarer types of pathogenic variants (eg, MEIs) to produce accurate genetic diagnostics.