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The frequency and efficacy of genetic testing in individuals with scimitar syndrome

Published online by Cambridge University Press:  02 July 2021

Tyler A. Fick Open the ORCID record for Tyler A. Fick [Opens in a new window] ,
Daryl A. Scott ,
Philip J. Lupo ,
Justin Weigand  and
Shaine A. Morris Open the ORCID record for Shaine A. Morris [Opens in a new window]
Tyler A. Fick
Affiliation:
Department of Pediatrics, Section of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas, USA
Daryl A. Scott
Affiliation:
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
Philip J. Lupo
Affiliation:
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA
Justin Weigand
Affiliation:
Department of Pediatrics, Section of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas, USA
Shaine A. Morris*
Affiliation:
Department of Pediatrics, Section of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas, USA
*
Author for correspondence: Shaine A. Morris, MD, MPH, Department of Pediatrics, Section of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, 6651 Main St, Legacy Tower, E1920, Houston, Texas, USA. Tel: 832–824–8278. E-mail: shainem@bcm.edu
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Abstract

Background:

Scimitar syndrome is a rare CHD composed of partial anomalous pulmonary venous connection from the right lung, via a scimitar vein, to the inferior vena cava rather than the left atrium. Genetic conditions associated with scimitar syndrome have not been well investigated at present.

Methods:

Our study included patients with scimitar syndrome diagnosed at Texas Children’s Hospital from January 1987 to July 2020. Medical records were evaluated to determine if genetic testing was performed, including chromosomal microarray analysis or whole-exome sequencing. Copy number variants identified as pathogenic/likely pathogenic and variants of unknown significance were collected. Analyses of cardiac and extracardiac findings were performed via chart review.

Results:

Ninety-eight patients were identified with scimitar syndrome, 89 of which met inclusion criteria. A chromosome analysis or chromosomal microarray analysis was performed in 18 patients (20%). Whole-exome sequencing was performed in six patients following negative chromosomal microarray analysis testing. A molecular genetic diagnosis was made in 7 of 18 cases (39% of those tested). Ninety-six per cent of the cohort had some type of extracardiac finding, with 43% having asthma and 20% having a gastrointestinal pathology. Of the seven patients with positive genetic testing, all had extracardiac anomalies with all but one having gastrointestinal findings and 30% having congenital diaphragmatic hernia.

Conclusions:

Genetic testing revealed an underlying diagnosis in roughly 40% of those tested. Given the relatively high prevalence of pathogenic variants, we recommend chromosomal microarray analysis and whole-exome sequencing for patients with scimitar syndrome and extracardiac defects.

Keywords

Scimitar syndromepulmonary veincardiogeneticsCHD
Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 4 , April 2022 , pp. 550 - 557
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Gudjonsson, U, Brown, JW. Scimitar syndrome. Pediatr Card Surg Annu. Published online 2006. doi: 10.1053/j.pcsu.2006.02.011.Google ScholarPubMed
Wang, H, Kalfa, D, Rosenbaum, MS, et al. Scimitar syndrome in children and adults: natural history, outcomes, and risk analysis. Ann Thorac Surg. Published online 2018. doi: 10.1016/j.athoracsur.2017.06.061.Google ScholarPubMed
van Nisselrooij, AEL, Lugthart, MA, Clur, SA, et al. The prevalence of genetic diagnoses in fetuses with severe congenital heart defects. Genet Med. Published online 2020. doi: 10.1038/s41436-020-0791-8.CrossRefGoogle ScholarPubMed
Pierpont, ME, Brueckner, M, Chung, WK, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement from the American Heart Association. Circulation. Published online 2018. doi: 10.1161/CIR.0000000000000606.CrossRefGoogle ScholarPubMed
Acevedo, JM, Lee, S, Gotteiner, N, Lay, AS, Patel, A. Total anomalous pulmonary venous connection (TAPVC): A familial cluster of 3 siblings. Echocardiography. Published online 2017. doi: 10.1111/echo.13665.CrossRefGoogle ScholarPubMed
Li, J, Yang, S, Pu, Z, et al. Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population. Oncotarget. Published online 2017. doi: 10.18632/oncotarget.15434.Google Scholar
Osio, D, Jain, N, Archer, N, Turnpenny, PD. Total anomalous pulmonary venous drainage in a patient with Koolen syndrome (del17q21.31). Clin Dysmorphol. Published online 2015. doi: 10.1097/MCD.0000000000000082.CrossRefGoogle Scholar
Nash, D, Arrington, CB, Kennedy, BJ, et al. Shared segment analysis and next-generation sequencing implicates the retinoic acid signaling pathway in Total Anomalous Pulmonary Venous Return (TAPVR). PLoS One. Published online 2015. doi: 10.1371/journal.pone.0131514.CrossRefGoogle Scholar
Evans, WN, Acherman, RJ, Ciccolo, ML, Castillo, WJ, Restrepo, H. An increased incidence of total anomalous pulmonary venous connection among Hispanics in Southern Nevada. Congenit Heart Dis. Published online 2015. doi: 10.1111/chd.12199.CrossRefGoogle ScholarPubMed
Ashida, K, Itoh, A, Naruko, T, et al. Familial scimitar syndrome: three-dimensional visualization of anomalous pulmonary vein in young sisters. Circulation. Published online 2001. doi: 10.1161/hc2501.092742.CrossRefGoogle ScholarPubMed
Trinca, M, Rey, C, Breviere, GM, Vaksmann, G, Francart, C, Dupuis, C. Familial form of the scimitar syndrome | LE SYNDROME DU CIMETERRE A FORME FAMILIALE. Arch Mal Coeur Vaiss. 1993; 86: 635–638.Google ScholarPubMed
Ruggieri, M, Abbate, M, Parano, E, Distefano, A, Guarnera, S, Pavone, L. Scimitar vein anomaly with multiple cardiac malformations, craniofacial, and central nervous system abnormalities in a brother and sister: familial scimitar anomaly or new syndrome? Am J Med Genet. Published online 2003. doi: 10.1002/ajmg.a.10115.CrossRefGoogle ScholarPubMed
Aklilu, TM, Adhana, MC, Aboye, AG. Imperforate anus associated with anomalous pulmonary venous return in scimitar syndrome. Case report from a tertiary hospital in Ethiopia. BMC Pediatr. Published online 2019. doi: 10.1186/s12887-019-1643-z.CrossRefGoogle ScholarPubMed
Lloyd, IE, Rowe, LR, Erickson, LK, Paxton, CN, South, ST, Alashari, M. Two cases of Scimitar syndrome associated with multiple congenital skeletal anomalies and lacking abnormalities by genomic microarray analysis. Pediatr Dev Pathol. Published online 2014. doi: 10.2350/14-04-1474-CR.1.CrossRefGoogle ScholarPubMed
Richards, S, Aziz, N, Bale, S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. Published online 2015. doi: 10.1038/gim.2015.30.CrossRefGoogle ScholarPubMed
De La Rochebrochard, C, Joly-Hélas, G, Goldenberg, A, et al. The intrafamilial variability of the 22q11.2 microduplication encompasses a spectrum from minor cognitive deficits to severe congenital anomalies [3]. Am J Med Genet Part A. Published online 2006. doi: 10.1002/ajmg.a.31227.CrossRefGoogle Scholar
Hasten, E, McDonald-McGinn, DM, Crowley, TB, et al. Dysregulation of TBX1 dosage in the anterior heart field results in congenital heart disease resembling the 22q11.2 duplication syndrome. Hum Mol Genet. Published online 2018. doi: 10.1093/hmg/ddy078.CrossRefGoogle ScholarPubMed
Guo, DC, Regalado, E, Casteel, DE, et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. Published online 2013. doi: 10.1016/j.ajhg.2013.06.019.CrossRefGoogle ScholarPubMed
Tang, M, Yang, YF, Xie, L, et al. Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability. Am J Med Genet Part A. Published online 2015. doi: 10.1002/ajmg.a.37347.CrossRefGoogle ScholarPubMed
Erdogan, F, Belloso, JM, Gabau, E, et al. Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital heart disease and microcephaly. Eur J Med Genet. Published online 2008. doi: 10.1016/j.ejmg.2007.09.007.CrossRefGoogle Scholar
Sugiura, N, Adams, SM, Corriveau, RA. An evolutionarily conserved N-terminal acetyltransferase complex associated with neuronal development. J Biol Chem. Published online 2003. doi: 10.1074/jbc.M301218200.CrossRefGoogle ScholarPubMed
Ritter, A, Berger, JH, Deardorff, M, et al. Variants in NAA15 cause pediatric hypertrophic cardiomyopathy. Am J Med Genet Part A. Published online 2020. doi: 10.1002/ajmg.a.61928.Google ScholarPubMed
Longoni, M, Pober, BR, High, FA. Congenital Diaphragmatic Hernia overview 1. Clinical characteristics of congenital Diaphragmatic Hernia clinical description. Gene Reviews. University of Washington, Seattle, 2019.Google Scholar
Qi, H, Yu, L, Zhou, X, et al. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. Published online 2018. doi: 10.1371/journal.pgen.1007822.CrossRefGoogle ScholarPubMed
Pinz, H, Pyle, LC, Li, D, et al. De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. Am J Med Genet Part A. Published online 2018. doi: 10.1002/ajmg.a.38620.CrossRefGoogle ScholarPubMed
Rossetti, LZ, Glinton, K, Yuan, B, et al. Review of the phenotypic spectrum associated with haploinsufficiency of MYRF. Am J Med Genet Part A. Published online 2019. doi: 10.1002/ajmg.a.61182.CrossRefGoogle ScholarPubMed
Stevens, CA, Bhakta, MG. Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet. Published online 1995. doi: 10.1002/ajmg.1320590313.CrossRefGoogle ScholarPubMed
Warburton, D, Ronemus, M, Kline, J, et al. The contribution of de novo and rare inherited copy number changes to congenital heart disease in an unselected sample of children with conotruncal defects or hypoplastic left heart disease. Hum Genet. Published online 2014. doi: 10.1007/s00439-013-1353-9.CrossRefGoogle ScholarPubMed
El Khattabi, LA, Heide, S, Caberg, JH, et al. 16p13.11 microduplication in 45 new patients: Refined clinical significance and genotype-phenotype correlations. J Med Genet. Published online 2020. doi: 10.1136/jmedgenet-2018-105389.Google Scholar
Kuang, SQ, Guo, DC, Prakash, SK, et al. Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections. PLoS Genet. Published online 2011. doi: 10.1371/journal.pgen.1002118.CrossRefGoogle ScholarPubMed
Erhart, P, Brandt, T, Straub, BK, et al. Familial aortic disease and a large duplication in chromosome 16p13.1. Mol Genet Genomic Med. Published online 2018. doi: 10.1002/mgg3.371.CrossRefGoogle Scholar
Gayther, SA, Batley, SJ, Linger, L, et al. Mutations truncating the EP300 acetylase in human cancers. Nat Genet. Published online 2000. doi: 10.1038/73536.CrossRefGoogle ScholarPubMed
Sugiura, N, Patel, RG, Corriveau, RA. N-Methyl-D-aspartate Receptors regulate a group of transiently expressed genes in the developing brain. J Biol Chem. Published online 2001. doi: 10.1074/jbc.M100011200.CrossRefGoogle ScholarPubMed
Koenning, M, Jackson, S, Hay, CM, et al. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci. Published online 2012. doi: 10.1523/JNEUROSCI.1069-12.2012.CrossRefGoogle ScholarPubMed
Cao, R, Liu, S, Liu, C, et al. Duplication and deletion of 22q11 associated with anomalous pulmonary venous connection. Pediatr Cardiol. Published online 2018. doi: 10.1007/s00246-017-1794-3.CrossRefGoogle ScholarPubMed
Therman, E, Susman, B. The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis. Hum Genet. Published online 1990. doi: 10.1007/BF00193192.CrossRefGoogle ScholarPubMed
Nagamani, SCS, Erez, A, Bader, P, et al. Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet. Published online 2011. doi: 10.1038/ejhg.2010.184.CrossRefGoogle ScholarPubMed
Kayawake, H, Motoyama, H, Date, H. Variant scimitar syndrome with intralobar pulmonary sequestration containing adenocarcinoma. Gen Thorac Cardiovasc Surg 2020; 68: 74–76. doi: 10.1007/s11748-019-01098-3.CrossRefGoogle ScholarPubMed
Gonzalez, M, Bize, P, Ris, HB, Krueger, T. Scimitar syndrome in association with intrapulmonary sequestration. Eur J Cardio-thoracic Surg 2011; 40: 273. doi: 10.1016/j.ejcts.2010.11.033.CrossRefGoogle ScholarPubMed
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