De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes

Watkins, W. Scott; Hernandez, E. Javier; Wesołowski, Sergiusz; Bisgrove, Brent W.; Sunderland, Ryan T.; Lin, Edwin; Lemmon, Gordon; Demarest, Bradley L.; Miller, Thomas A.; Bernstein, Daniel; Brueckner, Martina; Chung, Wendy K.; Gelb, Bruce D.; Goldmuntz, Elizabeth; Newburger, Jane W.; Seidman, Christine E.; Shen, Yufeng; Yost, H. Joseph; Yandell, Mark; Tristani‐Firouzi, Martin

doi:10.1038/s41467-019-12582-y

Cited by 69 publications

(98 citation statements)

References 38 publications

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“…Our findings show that SORBS2 regulates SHH and NOTCH signaling. It might interact with other components of SHH and NOTCH signaling pathways to modify cardiac phenotype, which is consistent with a recent report indicating cilia-related genes are significantly enriched for damaging rare recessive and compound heterozygous genotypes (48).…”

Section: Discussionsupporting

confidence: 92%

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Liang

Zhang

Wang

et al. 2020

Preprint

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24Chromosome 4q deletion is one of the most frequently detected genomic imbalance events 25 in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions 26 do not include known CHD genes. Alignment of those 4q deletions defined a minimal 27 overlapping region including only one gene-SORBS2. Histological analysis of Sorbs2 -/heart 28 revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically, SORBS2 had 29 a dual role in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of 30 second heart field (SHF) progenitors through c-ABL/NOTCH/SHH axis. In a targeted 31 sequencing of a panel of known and candidate CHD genes on 300 CHD cases, we found that 32 rare SORBS2 variants were significantly enriched in CHD patients. Our findings indicate that 33 SORBS2 is a regulator of cardiac development and its haploinsufficiency may contribute to 34 cardiac phenotype of 4q deletion syndrome. The presence of double atrial septum in Sorbs2 -/-35 hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical 36 thromboembolism. 37 38 39 Keywords: 4q deletion syndrome, Congenital heart disease, SORBS2, second heart field, 40 Notch1 41 42 3 Introduction 43Congenital heart disease (CHD) is present in ~1% newborns (1). Although CHD is the most 44 common birth defect, the underlying causes of most CHDs remain elusive. Genetic 45 heterogeneity and gene-environment interaction limit the genotype-phenotype correlation and 46 complicate interpretation of CHD genetics. Anatomic rectification through interventional and 47 surgical treatments have greatly improved survival rate of CHD patients (2). However, the same 48 medical treatment often yields different outcomes in different CHD patients, suggesting the 49 underlying genetic lesion impacts CHD prognosis. Therefore, elucidation of CHD genetic basis 50 is becoming ever more important in both reducing short-term therapeutic complications and 51 improving long-term care of CHD patients. With the advances in genetic diagnosis techniques, 52 the discovery of genetic variants is no longer a limit (3). The interpretation of the association 53 of identified genetic variants with phenotype becomes the imperative need to address the 54 genetic basis of CHD. 55CNV is a chromosomal structural aberration comprising of deletion or duplication with a 56 size larger than 1kb. Due to the abundance of low-copy repeats and retrotransposons, CNVs 57 are quite common genetic variants in human genomes. Previous studies have estimated that 58 CNVs contribute to 10-15% CHD (4, 5). The most common chromosomal deletion is 59 Del22q11.2, which is the shared genetic cause of 3 clinical syndromes-DiGeorge syndrome, 60 velocardiofacial syndrome and conotruncal anomaly face syndrome (6). The common forms of 61 Del22q11.2 are ~3 or 1.5 Mbs deletion encompassing dozens of genes (6). The successful 62 identification of the major CHD gene TBX1 has greatly advanced our understanding of the 63 pathogenesis of 22q11.2 del...

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Section: Discussionsupporting

confidence: 92%

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Liang

Zhang

Wang

et al. 2020

Preprint

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“…The well-established environmental factors underlying CHD include maternal conditions (such as innutrition, viral infection and endocrine disorder) and exposures to toxic chemicals, therapeutic drugs, or ionizing radiation during pregnancy (Patel and Burns, 2013). However, increasing studies underscore the genetic defects underpinning CHD, and variations in over 70 genes, encompassing those encoding transcription factors, signaling molecules, and sarcomeric proteins, have been involved in CHD (Bashamboo et al, 2018;Cantù et al, 2018;Jaouadi et al, 2018;Li et al, 2018a,c;Lombardo et al, 2018;Manheimer et al, 2018;Pierpont et al, 2018;Razmara and Garshasbi, 2018;Stephen et al, 2018;Xu et al, 2018;Yu Z et al, 2018;Alankarage et al, 2019;Gao et al, 2019;Kalayinia et al, 2019Kalayinia et al, , 2020Ma et al, 2019;Wang J et al, 2019, Wang Z et al, 2019Watkins et al, 2019;Zhu et al, 2019;Faucherre et al, 2020;Shabana et al, 2020;Zhao et al, 2020). Among the recognized CHD-causative genes, the majority code for cardiac transcription factors, encompassing TBX5, GATA4, and NKX2-5 (Li and Yang, 2017).…”

Section: Introductionmentioning

confidence: 99%

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

Jiang

Zhao

et al. 2020

Genet. Mol. Biol.

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“…De novo mutations may account for up to 10% of CHD cases [ 26 ], with an increased prevalence among patients where CHD is accompanied by extra-cardiac abnormalities such as neurodevelopmental disorders [ 24 ]. More recently, exome sequencing of approximately 2500 trios suggested distinct gene pathways associated with de novo and recessive forms of CHD, with mutations in chromatin-modifying genes being enriched in de novo sporadic cases [ 27 ].…”

Section: Genetic Association Studies In Cardiovascular Diseasementioning

confidence: 99%

The contribution of non-coding regulatory elements to cardiovascular disease

et al. 2020

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Cardiovascular disease collectively accounts for a quarter of deaths worldwide. Genome-wide association studies across a range of cardiovascular traits and pathologies have highlighted the prevalence of common non-coding genetic variants within candidate loci. Here, we review genetic, epigenomic and molecular approaches to investigate the contribution of non-coding regulatory elements in cardiovascular biology. We then discuss recent insights on the emerging role of non-coding variation in predisposition to cardiovascular disease, with a focus on novel mechanistic examples from functional genomics studies. Lastly, we consider the clinical significance of these findings at present, and some of the current challenges facing the field.

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De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes

Cited by 69 publications

References 38 publications

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

The contribution of non-coding regulatory elements to cardiovascular disease

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