A loss‐of‐function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF)

Peng, Jiayu; Wang, Qingjie; Meng, Zhijun; Wang, Jian; Zhou, Yue; Zhou, Shuang; Song, Wenting; Sun, Chen; Chen, Alex F.; Kim, Sun

doi:10.1002/2211-5463.13044

Cited by 5 publications

(3 citation statements)

References 39 publications

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“…Highlighting the genetic variability of TOF; 16 additional patients have been identified to have one pathogenic/likely pathogenic variant (11 loss of function and five missense) in 16 CHD genes ( ARHGAP31, ATRX, CACNA1C, CHD7, CSNK2A1, DLL4, EP300, GATAD2B, KAT6A, LZTR1, NF1, NODAL, PIK3CA, RAF1, RASA1, and SMAD2 ) and one patient has been identified with loss of function variants in two genes ( ASXL1 and PSMD12 ) ( Reuter et al, 2019 ). In addition, recent studies have shown that new variants found in TOF cases in the NDRG4 gene cause multiple heart abnormalities ( Peng et al, 2021 ). Evidence suggests that SMARCC2 is required for cardiac development by promoting cardiac myocyte differentiation and controlling temporal steps in cardiac differentiation ( Hota et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic insights into non-syndromic Tetralogy of Fallot

Althali

Hentges

2022

Front. Physiol.

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Congenital heart defects (CHD) include structural abnormalities of the heart or/and great vessels that are present at birth. CHD affects around 1% of all newborns worldwide. Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital cardiac abnormality, affecting three out of every 10,000 live infants with a prevalence rate of 5–10% of all congenital cardiac defects. The four hallmark characteristics of TOF are: right ventricular hypertrophy, pulmonary stenosis, ventricular septal defect, and overriding aorta. Approximately 20% of cases of TOF are associated with a known disease or chromosomal abnormality, with the remaining 80% of TOF cases being non-syndromic, with no known aetiology. Relatively few TOF patients have been studied, and little is known about critical causative genes for non-syndromic TOF. However, rare genetic variants have been identified as significant risk factors for CHD, and are likely to cause some cases of TOF. Therefore, this review aims to provide an update on well-characterized genes and the most recent variants identified for non-syndromic TOF.

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Section: Introductionmentioning

confidence: 99%

Genetic insights into non-syndromic Tetralogy of Fallot

Althali

Hentges

2022

Front. Physiol.

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“…We have conducted many disease-oriented population sequencing experiments and further improved in vitro and in vivo experiments to screen-out suspected pathogenic genes and mutation sites. We reported several pathogenic genes and variants associated with CHD, including SOX7 , [75] TBX1 , [76] NDRG4 , [77] and FOXH1 . [78] The data are helpful for the establishment of genes and phenotypes database of the Chinese population, and provide a basis for precise clinical diagnosis of CHD etiology.…”

Section: Construction Of Xinhua Intrauterine Diagnosis Systemmentioning

confidence: 99%

The Construction of an Intrauterine Diagnosis and Treatment System and Comprehensive Lifecycle Health Service of Congenital Heart Disease: Xinhua Hospital Model

Jiang

Wang

et al. 2023

Cardiology Discovery

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With the growing influence of slow population growth and population aging, China has established the birth policy and issued a series of documents to promote maternal and fetal health and improve the birth rate. With the increase in prevalence of birth defects, timely diagnosis and intervention in utero provide possibilities to reduce unnecessary abortions and offer better prognosis. Congenital heart disease (CHD), as one of the most common congenital birth defects, is the leading cause of mortality in patients aged <5 years, and brings a heavy burden to both the affected families and society. Fetuses with CHD are associated with an increased risk of pregnancy-related complications and premature birth, and children with CHD typically face growth and developmental problems even after the correction of malformation. Therefore, management including diagnosis, treatment, and rehabilitation throughout the fetal period into childhood and even adulthood is essential for children with CHD. Based on the rapid advances in intrauterine and perinatal medicine and an in-depth collaboration among obstetrics and pediatrics, a novel diagnosis and treatment system has been established for the management of CHD in the past 2 decades in Shanghai Xinhua Hospital. This Intrauterine Diagnosis and Treatment System and Comprehensive Lifecycle Health Service of Congenital Heart Disease model provides prenatal diagnosis, intrauterine intervention, delivery room service and neonatal therapies, and postintrauterine rehabilitation for children with CHD. We have developed a four-dimensional spatiotemporal image correlation echocardiography and a three-dimensional cardiac virtual endoscopy system for the intrauterine diagnosis of CHD, dramatically raising the diagnostic utility. Our innovative and independent newborn-intervention technique has effectively reduced the re-intervention rate in patients with pulmonary atresia with intact ventricular septum and critical pulmonary stenosis. In 2018, Xinhua Hospital independently performed the case of fetal aortic valvuloplasty in Asia through a multidepartment collaborative effort. All children treated in this system achieved biventricular circulation and a better long-term postoperative outcome. We also have conducted postoperative rehabilitation therapy to promote the development and health of children with CHD. The practice of Xinhua model has reduced unnecessary abortion of CHD fetuses, reduced the mortality rate associated with critical CHD, and improved the mid- and long-term prognosis in CHD, which is essential to promote the fertility level and children’s health. Furthermore, translational medicine platform and the birth cohort Early Life Plan was constructed to explore the origins of major developmental diseases and establish an early intervention model in CHD. This practice of assessment of the intrauterine system has been expanded to other congenital defects in Xinhua Hospital, and sequential treatment of more than 2,000 cases has been completed to date. Based on practice in intrauterine management of CHD and other diseases, the concept of Intrauterine Pediatrics was proposed as a first to emphasize early prevention and intervention of childhood diseases and promote a comprehensive lifecycle service for children. The development and evolution of this system requires further attention not only from researchers but also from the government and global medical communities.

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“… 12 Peng et al have revealed that the p.T256M variant in NDRG4 is a pathogenic variant associated with the impaired proliferation of human cardiomyocytes and cell cycle arrest, which may be involved in the pathogenesis of VSD. 13 Taken together, genetic factors are crucial in the occurrence of VSD. However, some genetic variants associated with VSD in the Chinese Tibetan population remain to be further identified.…”

Section: Introductionmentioning

confidence: 99%

NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 Genetic Variations are Associated with Ventricular Septal Defect in the Chinese Tibetan Population Through Whole-Exome Sequencing

Zhang¹,

Zhen²,

Li³

et al. 2023

PGPM

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Background Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD. Methods Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD. Results A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp). Conclusion This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.

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A loss‐of‐function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF)

Abstract: A loss-of-function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF)

Cited by 5 publications

References 39 publications

Genetic insights into non-syndromic Tetralogy of Fallot

Genetic insights into non-syndromic Tetralogy of Fallot

The Construction of an Intrauterine Diagnosis and Treatment System and Comprehensive Lifecycle Health Service of Congenital Heart Disease: Xinhua Hospital Model

NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 Genetic Variations are Associated with Ventricular Septal Defect in the Chinese Tibetan Population Through Whole-Exome Sequencing

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