Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is associated with numerous genes, especially those of the sarcomere family. The titin gene (TTN) consists of 365 exons and encodes the largest sarcomere protein (titin) in our bodies. Titin is associated with many diseases, such as hypertrophic cardiomyopathy and DCM. Here we screened three Chinese families affected by DCM, and found that each harbors a stop-gain or splice site mutation in TTN (c.G20137T,c. G52522T,c.44610-2A>C). Assessment of the probands by electrocardiogram, B-mode echocardiography, and cardiac magnetic resonance imaging revealed impaired cardiac function, arrhythmia, or abnormal cardiac structure. In conclusion, using whole exome sequencing, we found three unreported TTN mutations associated with DCM. This has expanded the TTN mutation spectrum of Chinese DCM patients, especially in Henan, the most populous province. These data provide new genetic targets for the diagnosis and treatment of DCM, and will increase our understanding of the relationship between TTN mutation and DCM clinical symptoms.

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Whole Exome Sequencing Identifies a Troponin T Mutation Hot Spot in Familial Dilated Cardiomyopathy

PLoS ONE ◽

10.1371/journal.pone.0078104 ◽

2013 ◽

Vol 8 (10) ◽

pp. e78104 ◽

Cited By ~ 25

Author(s):

Nzali Campbell ◽

Gianfranco Sinagra ◽

Kenneth L. Jones ◽

Dobromir Slavov ◽

Katherine Gowan ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Troponin T ◽

Hot Spot ◽

Familial Dilated Cardiomyopathy ◽

Whole Exome

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WHOLE EXOME SEQUENCING IDENTIFIES A TROPONIN T MUTATION HOT SPOT IN FAMILIAL DILATED CARDIOMYOPATHY

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(13)60594-x ◽

2013 ◽

Vol 61 (10) ◽

pp. E594

Author(s):

Luisa Mestroni ◽

Nzali Campbell ◽

Gianfranco Sinagra ◽

Kenneth Jones ◽

Dobromir Slavov ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Troponin T ◽

Hot Spot ◽

Familial Dilated Cardiomyopathy ◽

Whole Exome

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A novel heterozygous variant p.(Trp538Arg) of SYNM is identified by whole‐exome sequencing in a Chinese family with dilated cardiomyopathy

Annals of Human Genetics ◽

10.1111/ahg.12287 ◽

2018 ◽

Vol 83 (2) ◽

pp. 95-99 ◽

Cited By ~ 3

Author(s):

Shu‐Bing Zhang ◽

Yu‐Xing Liu ◽

Liang‐Liang Fan ◽

Hao Huang ◽

Jing‐Jing Li ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Family ◽

Whole Exome ◽

Heterozygous Variant

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Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy

Cardiology ◽

10.1159/000447422 ◽

2016 ◽

Vol 136 (1) ◽

pp. 10-14 ◽

Cited By ~ 5

Author(s):

Ji-Shi Liu ◽

Liang-Liang Fan ◽

Hao Zhang ◽

Xiaoxian Liu ◽

Hao Huang ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Nonsense Mutation ◽

Novel Mutations ◽

Chinese Families ◽

Structure Changes ◽

Whole Exome ◽

Gene Filtering

Objectives: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. Methods: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations. Sanger sequencing was applied to confirm the mutation cosegregation in the affected families. Results: A nonsense mutation (c.12325C>T/p.R4109X) and a missense mutation (c.17755G>C/p.G5919R) of TTN were identified in 2 Chinese DCM families, respectively. Both mutations were cosegregated in all affected members of both families. The nonsense mutation is predicted to result in a truncated TTN protein and the missense mutation leads to a substitution of glycine by arginine. Both variants may cause the structure changes of titin protein. Conclusions: We employed WES to detect the mutations of DCM patients and identified 2 novel mutations. Our study expands the spectrum of TTN mutations and offers accurate genetic testing information for DCM patients who are still clinically negative.

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Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family

Cardiology in the Young ◽

10.1017/s1047951121004455 ◽

2021 ◽

pp. 1-6

Author(s):

Mohammad Mahdavi ◽

Neda Mohsen-Pour ◽

Majid Maleki ◽

Mahshid Hesami ◽

Niloofar Naderi ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Molecular Diagnostic ◽

Metabolic Parameter ◽

Compound Heterozygous ◽

Formidable Challenge ◽

Whole Exome ◽

Iranian Family ◽

Compound Heterozygous Variants

Abstract Background: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. Method: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. Results: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. Conclusions: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

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