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Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy.

Zhao Y, Feng Y, Zhang YM, Ding XX, Song YZ, Zhang AM, Liu L, Zhang H, Ding JH, Xia XS - Biomed Res Int (2015)

Bottom Line: Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy.FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect.In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Science and Technology, Center for Molecular Diagnosis in Yunnan Province, Kunming University of Science and Technology, Kunming 650500, China.

ABSTRACT
As a common cardiac disease mainly caused by gene mutations in sarcomeric cytoskeletal, calcium-handling, nuclear envelope, desmosomal, and transcription factor genes, inherited cardiomyopathy is becoming one of the major etiological factors of sudden cardiac death (SCD) and heart failure (HF). This disease is characterized by remarkable genetic heterogeneity, which makes it difficult to screen for pathogenic mutations using Sanger sequencing. In the present study, three probands, one with familial hypertrophic cardiomyopathy (FHCM) and two with familial dilated cardiomyopathy (FDCM), were recruited together with their respective family members. Using next-generation sequencing technology (NGS), 24 genes frequently known to be related to inherited cardiomyopathy were screened. Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy. FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect. In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic.

No MeSH data available.


Related in: MedlinePlus

The pedigrees of the families with hypertrophic and dilated cardiomyopathy. Male family members are indicated by squares; female family members are indicated by circles, deceased individuals are indicated by symbols with a strikethrough, the unaffected individuals are represented by open symbols, and the solid symbols represent affected individuals. In addition, the probands are marked with a black arrow. The presence of a mutation was indicated by a “+” sign and the absence of mutations was indicated by a “–” sign. Family A: II: 3 is the proband, I: 1 and II: 2 died of sudden cardiac death, and III: 1 is clinically unaffected; the other clinical data were unavailable; Family B: II: 1 and II: 3 are the probands, II: 2 died of sudden cardiac death, and III: 1 mutation is present, but individual is clinically unaffected.
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fig2: The pedigrees of the families with hypertrophic and dilated cardiomyopathy. Male family members are indicated by squares; female family members are indicated by circles, deceased individuals are indicated by symbols with a strikethrough, the unaffected individuals are represented by open symbols, and the solid symbols represent affected individuals. In addition, the probands are marked with a black arrow. The presence of a mutation was indicated by a “+” sign and the absence of mutations was indicated by a “–” sign. Family A: II: 3 is the proband, I: 1 and II: 2 died of sudden cardiac death, and III: 1 is clinically unaffected; the other clinical data were unavailable; Family B: II: 1 and II: 3 are the probands, II: 2 died of sudden cardiac death, and III: 1 mutation is present, but individual is clinically unaffected.

Mentions: Families A and B were diagnosed with HCM and DCM, respectively; data regarding their clinical symptoms and the demographic information were collected during interviews. In family A, the proband II: 3 was a 44-year-old woman with clinical symptoms of dyspnoea and chest tightness after exercise. Her father (I: 1), sister (II: 1), and brother (II: 2) died of SCD around the age of 40 years. Her daughter (III: 1, 22 years of age) presented as clinically unaffected at the time of the interview (Figure 2(a)). No clinical data were available for III: 1. According to the clinical records of this proband (II: 3), her heart rate was 68 beats/min, and the ECGs showed changes in T-waves, which is common in patients with HCM. Additionally, the Q-wave was abnormal in the sidewalls, while the QRS (86 ms) duration was within the normal range (Figure 1(a)). Moreover, echocardiography showed an increase in the interventricular septum thickness (IVST, 14.8 mm), as well as in the thickening of the left atrium (LA, 32 mm).


Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy.

Zhao Y, Feng Y, Zhang YM, Ding XX, Song YZ, Zhang AM, Liu L, Zhang H, Ding JH, Xia XS - Biomed Res Int (2015)

The pedigrees of the families with hypertrophic and dilated cardiomyopathy. Male family members are indicated by squares; female family members are indicated by circles, deceased individuals are indicated by symbols with a strikethrough, the unaffected individuals are represented by open symbols, and the solid symbols represent affected individuals. In addition, the probands are marked with a black arrow. The presence of a mutation was indicated by a “+” sign and the absence of mutations was indicated by a “–” sign. Family A: II: 3 is the proband, I: 1 and II: 2 died of sudden cardiac death, and III: 1 is clinically unaffected; the other clinical data were unavailable; Family B: II: 1 and II: 3 are the probands, II: 2 died of sudden cardiac death, and III: 1 mutation is present, but individual is clinically unaffected.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4495182&req=5

fig2: The pedigrees of the families with hypertrophic and dilated cardiomyopathy. Male family members are indicated by squares; female family members are indicated by circles, deceased individuals are indicated by symbols with a strikethrough, the unaffected individuals are represented by open symbols, and the solid symbols represent affected individuals. In addition, the probands are marked with a black arrow. The presence of a mutation was indicated by a “+” sign and the absence of mutations was indicated by a “–” sign. Family A: II: 3 is the proband, I: 1 and II: 2 died of sudden cardiac death, and III: 1 is clinically unaffected; the other clinical data were unavailable; Family B: II: 1 and II: 3 are the probands, II: 2 died of sudden cardiac death, and III: 1 mutation is present, but individual is clinically unaffected.
Mentions: Families A and B were diagnosed with HCM and DCM, respectively; data regarding their clinical symptoms and the demographic information were collected during interviews. In family A, the proband II: 3 was a 44-year-old woman with clinical symptoms of dyspnoea and chest tightness after exercise. Her father (I: 1), sister (II: 1), and brother (II: 2) died of SCD around the age of 40 years. Her daughter (III: 1, 22 years of age) presented as clinically unaffected at the time of the interview (Figure 2(a)). No clinical data were available for III: 1. According to the clinical records of this proband (II: 3), her heart rate was 68 beats/min, and the ECGs showed changes in T-waves, which is common in patients with HCM. Additionally, the Q-wave was abnormal in the sidewalls, while the QRS (86 ms) duration was within the normal range (Figure 1(a)). Moreover, echocardiography showed an increase in the interventricular septum thickness (IVST, 14.8 mm), as well as in the thickening of the left atrium (LA, 32 mm).

Bottom Line: Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy.FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect.In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Science and Technology, Center for Molecular Diagnosis in Yunnan Province, Kunming University of Science and Technology, Kunming 650500, China.

ABSTRACT
As a common cardiac disease mainly caused by gene mutations in sarcomeric cytoskeletal, calcium-handling, nuclear envelope, desmosomal, and transcription factor genes, inherited cardiomyopathy is becoming one of the major etiological factors of sudden cardiac death (SCD) and heart failure (HF). This disease is characterized by remarkable genetic heterogeneity, which makes it difficult to screen for pathogenic mutations using Sanger sequencing. In the present study, three probands, one with familial hypertrophic cardiomyopathy (FHCM) and two with familial dilated cardiomyopathy (FDCM), were recruited together with their respective family members. Using next-generation sequencing technology (NGS), 24 genes frequently known to be related to inherited cardiomyopathy were screened. Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy. FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect. In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic.

No MeSH data available.


Related in: MedlinePlus