Dataset Information

Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients.

ABSTRACT:

Background

Myosin family genes, including those encoding myosin heavy chain 6, myosin heavy chain 7, myosin light chain 3, and myosin light chain 2 (MYL2), are important genetic factors in congenital heart disease (CHD). However, how these genes contribute to CHD in the Han Chinese population remains unclear.

Methods

We sequenced myosin family genes in a Han Chinese cohort comprising 412 CHD patients and 213 matched controls in the present study. A zebrafish model was used to evaluate the pathogenicity of rare mutations in MYL2.

Results

We identified 30 known mutations and 12 novel mutations. Furthermore, the contributions of two novel mutations, MYL2 p.Ile158Thr and p.Val146Met, to CHD were analyzed. The p.Ile158Thr mutation increased MYL2 expression. In zebrafish embryos, injection of myl2b-targeting morpholinos led to aberrant cardiac structures, an effect that was reversed by expression of wild-type MYL2 but not MYL2 p.Ile158Thr and pVal146Met.

Conclusions

Overall, our findings suggest that MYL2 p.Ile158Thr and p.Val146Met contribute to the etiology of CHD. The results also indicate the importance of MYL2 in heart formation.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC9544220 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients.

Zhang Yunqian Y Peng Rui R Wang Hongyan H

Molecular genetics & genomic medicine 20220822 10

<h4>Background</h4>Myosin family genes, including those encoding myosin heavy chain 6, myosin heavy chain 7, myosin light chain 3, and myosin light chain 2 (MYL2), are important genetic factors in congenital heart disease (CHD). However, how these genes contribute to CHD in the Han Chinese population remains unclear.<h4>Methods</h4>We sequenced myosin family genes in a Han Chinese cohort comprising 412 CHD patients and 213 matched controls in the present study. A zebrafish model was used to eval ...[more]

PMID: 35993536

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Project description:BackgroundHeterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx.MethodsWe collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models.ResultsNineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning.ConclusionsOur findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.

Dataset Information

Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients.

Background

Methods

Results

Conclusions

Publications

Identification and genetic analysis of rare variants in myosin family genes in 412 Han Chinese congenital heart disease patients.

Similar Datasets

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