Dataset Information

A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient.

ABSTRACT: The position and morphology of human internal organs are asymmetrically distributed along the left-right axis. Aberrant left-right patterning in the developing embryo can lead to a series of congenital laterality defects, such as dextrocardia and heterotaxy syndrome. Laterality defects are a genetic condition; however, pathogenic genetic lesions are found in only one-fifth of patients. In this study, whole-exome sequencing was conducted for 78 patients with laterality defects. We identified a novel stopgain variant in MMP21 (c.G496T; p.G166*) in a Chinese patient with mirror-image dextrocardia. This variant caused a truncated MMP21 mRNA containing only the signal peptide and propeptide, while the coding sequence of matrix metalloproteinase-21 was almost entirely absent. To the best of our knowledge, this novel variant is the first homozygous stopgain variant identified in dextrocardia patients, and the first MMP21 variant found in East Asia. Our findings expand the spectrum of MMP21 variants and provide support for the critical role of MMP21 during left-right patterning in the Han Chinese population.

SUBMITTER: Yuan ZZ

PROVIDER: S-EPMC7680847 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Novel Nonsense <i>MMP21</i> Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient.

Yuan Zhuang-Zhuang ZZ Fan Liang-Liang LL Jiang Zi-Chen ZC Yang Yi-Feng YF Tan Zhi-Ping ZP

Frontiers in cardiovascular medicine 20201109

The position and morphology of human internal organs are asymmetrically distributed along the left-right axis. Aberrant left-right patterning in the developing embryo can lead to a series of congenital laterality defects, such as dextrocardia and heterotaxy syndrome. Laterality defects are a genetic condition; however, pathogenic genetic lesions are found in only one-fifth of patients. In this study, whole-exome sequencing was conducted for 78 patients with laterality defects. We identified a no ...[more]

PMID: 33240936

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Project description:BackgroundHeterotaxy syndrome (HTX) is caused by aberrant left-right patterning early in embryonic development, which results in abnormal positioning and morphology of the thoracic and abdominal organs. Currently, genetic testing discerns the underlying genetic cause in less than 20% of sporadic HTX cases, indicating that genetic pathogenesis remains poorly understood. In this study, we aim to garner a deeper understanding of the genetic factors of this disease by documenting the effect of different matrix metalloproteinase 21 (MMP21) variants on disease occurrence and pathogenesis.MethodsEighty-one HTX patients with complex congenital heart defects and 89 healthy children were enrolled, and we investigated the pathogenetic variants related to patients with HTX by exome sequencing. Zebrafish splice-blocking Morpholino oligo-mediated transient suppression assays were performed to confirm the potential pathogenicity of missense variants found in these patients with HTX.ResultsThree MMP21 heterozygous non-synonymous variants (c.731G > A (p.G244E), c.829C > T (p.L277F), and c.1459A > G (p.K487E)) were identified in three unrelated Chinese Han patients with HTX and complex congenital heart defects. Sanger sequencing confirmed that all variants were de novo. Cell transfection assay showed that none of the variants affect mRNA and protein expression levels of MMP21. Knockdown expression of mmp21 by splice-blocking Morpholino oligo in zebrafish embryos revealed a heart looping disorder, and mutant human MMP21 mRNA (c.731G > A, c.1459A > G, heterozygous mRNA (wild-type&c.731G > A), as well as heterozygous mRNA (wild-type& c.1459A > G) could not effectively rescue the heart looping defects. A patient with the MMP21 p.G244E variant was identified with other potential HTX-causing missense mutations, whereas the patient with the MMP21 p.K487E variant had no genetic mutations in other causative genes related to HTX.ConclusionOur study highlights the role of the disruptive heterozygous MMP21 variant (p.K487E) in the etiology of HTX with complex cardiac malformations and expands the current mutation spectrum of MMP21 in HTX.

Dataset Information

A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient.

Publications

A Novel Nonsense <i>MMP21</i> Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient.

Similar Datasets

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