Rare copy number variants in a population‐based investigation of hypoplastic right heart syndrome

Dimopoulos, Aggeliki; Sicko, Robert J.; Kay, Denise M.; Rigler, Shannon L.; Druschel, Charlotte M.; Casini, Michèle; Browne, Marilyn L.; Fan, Ruzong; Romitti, Paul A.; Brody, Lawrence C.; Mills, James L.

doi:10.1002/bdra.23586

Cited by 10 publications

(10 citation statements)

References 41 publications

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“…Interfering ventricle-specific transcription factors and/or their effectors can cause sole ventricle developmental defects [ 9 ]. Hypoplastic right heart syndrome is a rare congenital heart disease that is characterized by an underdeveloped right ventricle [ 10 , 11 ]. However, the molecular mechanisms that regulate right ventricle development remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Liu

Wang

et al. 2017

Clinical & Translational Med

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Background Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cytoskeleton remodeling and cell polarity establishment. Inactivating Cdc42 in cardiomyocytes resulted in embryonic lethality with heart developmental defects, including ventricular septum defects and thin ventricle wall syndrome. Findings In this study, we have generated a Cdc42 cardiomyocyte knockout mouse line by crossing Cdc42/flox mice with myosin light chain 2a (MLC2a)-Cre mice. We found that the deletion of Cdc42 in embryonic cardiomyocytes resulted in an underdeveloped right ventricle. Microarray analysis and real-time PCR data analysis displayed that the deletion of Cdc42 decreased dHand expression level. In addition, we found evaginations in the ventricle walls of Cdc42 knockout hearts. Conclusion We concluded that Cdc42 plays an essential role in right ventricle growth.

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Section: Introductionmentioning

confidence: 99%

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Liu

Wang

et al. 2017

Clinical & Translational Med

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“…To the best of our knowledge, this is only the second population‐based study aiming to investigate the role of novel, rare copy number variations (CNVs) in the etiology of HRHS and expands on our previous work underscoring the potential importance of genetic factors in HRHS (Dimopoulos et al, ).…”

Section: Introductionmentioning

confidence: 77%

“…Hypoplastic right heart syndrome (HRHS) is a rare cyanotic congenital heart defect characterized by underdeveloped and malformed structures of the right heart (Dib, Araoz, Davies, Dearani, & Ammash, ). HRHS includes a wide range of abnormalities of varying severity that usually involve pulmonary valve atresia, underdevelopment of the right ventricle (RV), hypoplasia of the tricuspid valve, hypoplasia of the pulmonary artery, and atrial septal defect (CHD‐UK; Dib et al, ; Dimopoulos et al, ). Due to the rarity of the disease, the prevalence of HRHS is yet to be established, but it is reported to be less than that of the hypoplastic left heart syndrome, which occurs in four out of every 10,000 births (CHD‐UK; Gordon, Rodriguez, Lee, & Chang, ; Reller, Strickland, Riehle‐Colarusso, Mahle, & Correa, ).…”

Section: Introductionmentioning

confidence: 99%

“…Cases with severe malformations, such as atresia of the right ventricle outflow tract, right ventricle and tricuspid valve hypoplasia, along with coronary artery abnormalities present early with cyanosis and severe complications and require immediate intervention (“≤http://www.chd-uk.co.uk/types-of-chd-and-operations/hypoplastic-right-heart-syndrome-hrhs/%3e,”; Tworetzky et al, ). Less severe cases with only membranous atresia of the pulmonary valve and a relatively normal sized right ventricle may cause minimal or no postnatal cyanosis and remain undiagnosed until adulthood (Dib et al, ; Dimopoulos et al, ; Prasad, Singh, & Radhakrishnan, ).…”

Section: Introductionmentioning

confidence: 99%

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Copy number variants in hypoplastic right heart syndrome

Giannakou

Sicko

Kay

et al. 2018

American J of Med Genetics Pt A

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Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases.ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.

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“…DSCAM overexpression leads to congenital heart defects [ 56 ] and is probably responsible for the congenital heart defects observed in Down syndrome patients [ 57 ]. Moreover, SEMA3A and PRRX2 mutations also lead to congenital heart defects [ 58 , 59 ]. Next to its function in the heart, both proteins also influence smooth muscle development.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide methylation patterns in Marfan syndrome

et al. 2021

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Background Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process. Methods The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed. Results We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP’s that associated with clinical events. No significant associations at p < 10–8 or p < 10–6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18–22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before. Conclusion This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.

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Rare copy number variants in a population‐based investigation of hypoplastic right heart syndrome

Cited by 10 publications

References 41 publications

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Copy number variants in hypoplastic right heart syndrome

Genome-wide methylation patterns in Marfan syndrome

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