Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

Hagen, Erin M.; Sicko, Robert J.; Kay, Denise M.; Rigler, Shannon L.; Dimopoulos, Aggeliki; Ahmad, Shabbir; Doleman, Margaret H.; Fan, Ruzong; Romitti, Paul A.; Browne, Marilyn L.; Casini, Michèle; Brody, Lawrence C.; Shaw, Gary M.; Jelliffe‐Pawlowski, Laura L.; Mills, James L.

doi:10.1007/s00439-016-1727-x

Cited by 16 publications

(8 citation statements)

References 37 publications

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“…263,267 Clinically relevant CNVs have been identified in 15% to 26% of patients with heterotaxy syndrome. 268–272 Heterotaxy has the highest relative risk among all classes of congenital HDs, which supports a strong genetic component. 273 Autosomal dominant, autosomal recessive, and X-linked inheritance patterns have all been described, but unlike other types of congenital HD, de novo sequence variants are not major contributors to heterotaxy.…”

Section: Heterotaxy and Ciliopathiesmentioning

confidence: 71%

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association

Pierpont

Brueckner²,

Chung³

et al. 2018

Circulation

493

441

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This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientifi statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish as well as human induced pluripotent stem cell–based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care–related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.

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Section: Heterotaxy and Ciliopathiesmentioning

confidence: 71%

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association

Pierpont

Brueckner²,

Chung³

et al. 2018

Circulation

493

441

View full text Add to dashboard Cite

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“…In humans, mutations in several genes have been associated with Htx, including CFC1 , NODAL , ACVR2B , LEFTY2 , GDF1 , ZIC3 , CRELD1 , and NKX2.5 [ 6 – 13 ]. However, the mutations reported in these genes can explain only 10–20% of Htx cases; the underlying cause in the majority of patients remains unknown [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Rare copy number variants analysis identifies novel candidate genes in heterotaxy syndrome patients with congenital heart defects

Liu

Cao

et al. 2018

Genome Med

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BackgroundHeterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx.MethodsWe collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models.ResultsNineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning.ConclusionsOur findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0549-y) contains supplementary material, which is available to authorized users.

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“…When rhythm and situs anomalies were excluded, isolated IIVC was found in 0.08% (6/7250) of all cardiac examinations 0.6% (6/922) of all cardiac anomalies. Median maternal age was 30.5 years (range 21-38) and median gestational age at examination was 23 gestational weeks (range [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. The indication of referral for fetal echocardiography was IIVC in all cases.…”

Section: Resultsmentioning

confidence: 99%

Prenatal diagnosis of hepatic interruption of the inferior vena cava with azygos/hemiazygos continuation without structural heart defects: A case series

Babaoğlu

Doğan

Başar

et al. 2022

J of Clinical Ultrasound

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Objectives To describe fetal spectrum and echocardiographic characteristics of interrupted inferior vena cava (IIVC) with azygos/hemiazygous continuation without other structural heart defects and to evaluate its association with visceral heterotaxy and isomerism, extracardiac and genetic anomalies, and to review neonatal outcome. Methods This was a retrospective study of 14 fetuses with a confirmed diagnosis of IIVC with normal intracardiac anatomy. The following variables were collected; indication for referral, gestational age at diagnosis; associated isomerism and visceral heterotaxy, heart rhythm, genetic and extracardiac abnormalities, and fetal/neonatal outcome. Results Among 36 fetuses with IIVC, 14 cases (38.8%) had normal intracardiac anatomy. These IIVC cases correspond to 0.19% (14/7250) of all fetal cardiac examinations, and to 1.5% (14/922) of all cardiac abnormalities. Six patients had visceral abnormalities. Atrial appendage morphology was clearly depicted in three fetuses, both appendages were left. One fetus had bradyarrhythmia revealing atrial ectopic rhythm. Six fetuses did not have any concomitant cardiac or visceral abnormalities, therefore regarded as isolated. All babies were delivered at term with a good prognosis. Conclusion Our study has shown that almost half of the IIVC cases without intracardiac structural anomalies displayed other findings of isomerism while the other half was isolated benign vascular variant. Therefore, prenatal diagnosis of IIVC should prompt a comprehensive evaluation for cardiac, situs, and visceral anomalies. The outcome is favorable.

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Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways

Cited by 16 publications

References 37 publications

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association

Rare copy number variants analysis identifies novel candidate genes in heterotaxy syndrome patients with congenital heart defects

Prenatal diagnosis of hepatic interruption of the inferior vena cava with azygos/hemiazygos continuation without structural heart defects: A case series

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