外显子
生物
遗传学
选择性拼接
外显子跳跃
RNA剪接
表型
基因
核糖核酸
作者
Daniel J. Clemens,David J. Tester,Isabelle Marty,Michael J. Ackerman
出处
期刊:Heart Rhythm
[Elsevier]
日期:2020-06-01
卷期号:17 (6): 1017-1024
被引量:10
标识
DOI:10.1016/j.hrthm.2020.01.012
摘要
Background Triadin knockout syndrome (TKOS) is a rare arrhythmia syndrome caused by recessive null variants in TRDN-encoded cardiac triadin 1. TKOS has presented frequently with cardiac arrest in childhood. Objective The purpose of this study was to elucidate the underlying genetic mechanism of disease in a genetically elusive patient displaying a characteristic TKOS phenotype. Methods Genome sequencing and a TRDN gene–specific trio analysis were completed on the patient. RNA and protein isolated from patient-specific human-induced pluripotent stem cell-derived cardiomyocytes were used to determine the effects of the identified variants using reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Results Genome sequencing revealed compound heterozygous putative splice-error variants (maternal c.22+29A>G and paternal c.484+1189G>A). The novel paternally derived c.484+1189G>A variant is located within 24 base pairs of a predicted alternative exon 6 (exon 6a), which resides within the intron between canonical exons 5 and 6. We determined that this previously unrecognized exon 6a produces a short TRDN transcript and potentially a novel protein isoform in the normal human heart. The c.484+1189G>A variant not only results in abnormal splicing of the exon 6a–containing transcript leading to a frameshift mutation but also results in the abolishment of the 8-exon cardiac triadin 1 transcript. Conclusion Here, we present evidence for a novel alternative exon 6a–containing TRDN transcript in the normal heart. The novel deep intronic TRDN variant identified in a patient with TKOS leads to splicing error of a newly recognized exon 6a and loss of triadin. Considering that both TRDN variants in this patient were missed after commercial testing, these results highlight the importance of using genome sequencing when identifying patients with TKOS. Triadin knockout syndrome (TKOS) is a rare arrhythmia syndrome caused by recessive null variants in TRDN-encoded cardiac triadin 1. TKOS has presented frequently with cardiac arrest in childhood. The purpose of this study was to elucidate the underlying genetic mechanism of disease in a genetically elusive patient displaying a characteristic TKOS phenotype. Genome sequencing and a TRDN gene–specific trio analysis were completed on the patient. RNA and protein isolated from patient-specific human-induced pluripotent stem cell-derived cardiomyocytes were used to determine the effects of the identified variants using reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Genome sequencing revealed compound heterozygous putative splice-error variants (maternal c.22+29A>G and paternal c.484+1189G>A). The novel paternally derived c.484+1189G>A variant is located within 24 base pairs of a predicted alternative exon 6 (exon 6a), which resides within the intron between canonical exons 5 and 6. We determined that this previously unrecognized exon 6a produces a short TRDN transcript and potentially a novel protein isoform in the normal human heart. The c.484+1189G>A variant not only results in abnormal splicing of the exon 6a–containing transcript leading to a frameshift mutation but also results in the abolishment of the 8-exon cardiac triadin 1 transcript. Here, we present evidence for a novel alternative exon 6a–containing TRDN transcript in the normal heart. The novel deep intronic TRDN variant identified in a patient with TKOS leads to splicing error of a newly recognized exon 6a and loss of triadin. Considering that both TRDN variants in this patient were missed after commercial testing, these results highlight the importance of using genome sequencing when identifying patients with TKOS.
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