Dataset Information

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect.

ABSTRACT: Congenital heart disease (CHD) is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect (ASD) is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 (TBX20) contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G>A (p.D176N), was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs (SIFT, Polyphen2, and MutationTaster). This mutation was also not presented in the current Single Nucleotide Polymorphism Database (dbSNP) or National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree.

SUBMITTER: Liu JJ

PROVIDER: S-EPMC4162884 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect.

Liu Ji-jia JJ Fan Liang-liang LL Chen Jin-lan JL Tan Zhi-ping ZP Yang Yi-feng YF

Journal of Zhejiang University. Science. B 20140901 9

Congenital heart disease (CHD) is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect (ASD) is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 (TBX20) contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G>A (p.D176N), was identified an ...[more]

PMID: 25183037

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Project description:Atrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can affect almost all organs. Cardiac abnormalities vary greatly in congenital disorder of glycosylation type 1a and congenital heart defects have already been reported, but there is little knowledge about the effect of this inherited disorder on an existing congenital heart defect. Herein we report for the first time on a baby with congenital disorder of glycosylation type 1a with atrial septal defect and make a comparison of changes in atrial septal defect by follow-ups to the age of 3.Our patient was an 8-month-old Han Chinese boy. At the initial visit, he presented with recurrent lower respiratory infection, heart murmur, psychomotor retardation, inverted nipples, and cerebellar atrophy. Echocardiography revealed a 8 mm secundum atrial septal defect with left-to-right shunt (Qp/Qs ratio 1.6). Enzyme testing of phosphomannomutase 2 demonstrated decreased levels of phosphomannomutase 2 activities in fibroblasts. Whole exon sequencing showed he was heterozygous for a frameshift mutation (p.I153X) and a missense mutation (p.I132T) in PMM2 gene. The diagnosis of congenital disorder of glycosylation type 1a with atrial septal defect was issued. Now, he is 3-years old at the time of this writing, with the development of congenital disorder of glycosylation type 1a (cerebellar atrophy become more severe and the symptom of nystagmus emerged), the size of atrial septal defect increased to 10 mm and the Qp/Qs ratio increased to 1.9, which suggested exacerbation of the atrial septal defect. Congenital heart defect-associated gene sequencing is then performed and shows there are no pathogenic mutations, which suggested intrinsic cardiac factors are not the cause of exacerbation of the atrial septal defect in our patient and it is reasonable to assume congenital disorder of glycosylation type 1a can worsen the situation of the existing atrial septal defect.This report highlights the view that congenital disorders of glycosylation type 1a should be excluded when faced with congenital heart defect with cerebellar atrophy or neurodevelopmental delay, especially when the situation of congenital heart defect becomes more and more severe.

Project description:Background Delayed brain development, brain injury, and neurodevelopmental disabilities are commonly observed in infants operated for complex congenital heart defect. Our previous findings of poorer neurodevelopmental outcomes in individuals operated for simple congenital heart defects calls for further etiological clarification. Hence, we examined the microstructural tissue composition in cerebral cortex and subcortical structures in comparison to healthy controls and whether differences were associated with neurodevelopmental outcomes. Methods and Results Adults (n=62) who underwent surgical closure of an atrial septal defect (n=33) or a ventricular septal defect (n=29) in childhood and a group of healthy, matched controls (n=38) were enrolled. Brain diffusional kurtosis imaging and neuropsychological assessment were performed. Cortical and subcortical tissue microstructure were assessed using mean kurtosis tensor and mean diffusivity and compared between groups and tested for associations with neuropsychological outcomes. Alterations in microstructural tissue composition were found in the parietal, temporal, and occipital lobes in the congenital heart defects, with distinct mean kurtosis tensor cluster-specific changes in the right visual cortex (pericalcarine gyrus, P=0.002; occipital part of fusiform and lingual gyri, P=0.019). Altered microstructural tissue composition in the subcortical structures was uncovered in atrial septal defects but not in ventricular septal defects. Associations were found between altered cerebral microstructure and social recognition and executive function. Conclusions Children operated for simple congenital heart defects demonstrated altered microstructural tissue composition in the cerebral cortex and subcortical structures during adulthood when compared with healthy peers. Alterations in cerebral microstructural tissue composition were associated with poorer neuropsychological performance. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

Dataset Information

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect.

Publications

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect.

Similar Datasets

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