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Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return

European Journal of Human Genetics volume 31, pages 1430–1439 (2023)Cite this article

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Abstract

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes—EFTUD2, NAA15, and NKX2-1—for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.

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Fig. 1: Machine learning allows all RefSeq genes to be ranked based on their similarity to genes known to cause APVR.
Fig. 2: Study workflow.
Fig. 3: Copy number variants recurrently associated with APVR.

Data availability

The data generated during this study can be found within the published article and its supplementary files. All previously unpublished variants from the BG clinical database and the CCVM database have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/; SNVs = SCV003915701 - SCV003915719; CNVs = SCV003919100 - SCV003919143).

References

  1. Douglas YL, Jongbloed MR, Deruiter MC, Gittenberger-de Groot AC. Normal and abnormal development of pulmonary veins: state of the art and correlation with clinical entities. Int J Cardiol. 2011;147:13–24.

    PubMed  Google Scholar 

  2. Verma AK, Sethi S, Kohli N. Partial anomalous pulmonary venous connection: state-of-the-art review with assessment using a multidetector computed tomography angiography. Pol J Radio. 2022;87:e549–e56.

    Google Scholar 

  3. Bjornard K, Riehle-Colarusso T, Gilboa SM, Correa A. Patterns in the prevalence of congenital heart defects, metropolitan Atlanta, 1978 to 2005. Birth Defects Res A Clin Mol Teratol. 2013;97:87–94.

    CAS  PubMed  Google Scholar 

  4. Liu Y, Chen S, Zuhlke L, Black GC, Choy MK, Li N, et al. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019;48:455–63.

    PubMed  PubMed Central  Google Scholar 

  5. St Louis JD, Harvey BA, Menk JS, Raghuveer G, O’Brien JE Jr, Bryant R 3rd, et al. Repair of “simple” total anomalous pulmonary venous connection: a review from the Pediatric Cardiac Care Consortium. Ann Thorac Surg. 2012;94:133–7. discussion 137-8

    Google Scholar 

  6. Spigel ZA, Edmunds EE, Caldarone CA, Hickey EJ, Binsalamah ZM, Heinle JS. Total anomalous pulmonary venous connection: Influence of heterotaxy and venous obstruction on outcomes. J Thorac Cardiovasc Surg. 2022;163:387–95.e3.

    PubMed  Google Scholar 

  7. Hinton RB, McBride KL, Bleyl SB, Bowles NE, Border WL, Garg V, et al. Rationale for the cytogenomics of cardiovascular malformations consortium: a phenotype intensive registry based approach. J Cardiovasc Dev Dis. 2015;2:76–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: Database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet. 2009;84:524–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vulto-van Silfhout AT, van Ravenswaaij CM, Hehir-Kwa JY, Verwiel ET, Dirks R, van Vooren S, et al. An update on ECARUCA, the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations. Eur J Med Genet. 2013;56:471–4.

    PubMed  Google Scholar 

  10. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. 2015;17:405–24.

    PubMed  PubMed Central  Google Scholar 

  11. Scott TM, Campbell IM, Hernandez-Garcia A, Lalani SR, Liu P, Shaw CA, et al. Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH. J Med Genet. 2021;59:270–8.

    PubMed  Google Scholar 

  12. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245–57.

    PubMed  Google Scholar 

  13. Blake JA, Bult CJ, Eppig JT, Kadin JA, Richardson JE. Mouse Genome Database G. The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse. Nucleic Acids Res. 2014;42:D810–7.

    CAS  PubMed  Google Scholar 

  14. McKusick VA. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet. 2007;80:588–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Campbell IM, Rao M, Arredondo SD, Lalani SR, Xia Z, Kang SH, et al. Fusion of large-scale genomic knowledge and frequency data computationally prioritizes variants in epilepsy. PLoS Genet. 2013;9:e1003797.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Callaway DA, Campbell IM, Stover SR, Hernandez-Garcia A, Jhangiani SN, Punetha J, et al. Prioritization of candidate genes for congenital diaphragmatic hernia in a critical region on chromosome 4p16 using a machine-learning algorithm. J Pediatr Genet. 2018;7:164–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Rossetti LZ, Glinton K, Yuan B, Liu P, Pillai N, Mizerik E, et al. Review of the phenotypic spectrum associated with haploinsufficiency of MYRF. Am J Med Genet A 2019;179:1376–82.

    PubMed  PubMed Central  Google Scholar 

  18. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Collins RL, Glessner JT, Porcu E, Lepamets M, Brandon R, Lauricella C, et al. A cross-disorder dosage sensitivity map of the human genome. Cell 2022;185:3041–55.e25.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zou Y, Wu J, Wang G, Zhou C, Dong N. Infracardiac total anomalous pulmonary venous return in a patient with Williams syndrome: A case report. Med (Baltim). 2019;98:e16276.

    Google Scholar 

  21. Lalani SR, Shaw C, Wang X, Patel A, Patterson LW, Kolodziejska K, et al. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur J Hum Genet. 2013;21:173–81.

    CAS  PubMed  Google Scholar 

  22. Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, et al. Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res. 2009;105:956–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Meng L, Pammi M, Saronwala A, Magoulas P, Ghazi AR, Vetrini F, et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr. 2017;171:e173438.

    PubMed  PubMed Central  Google Scholar 

  24. Liu H, Giguet-Valard AG, Simonet T, Szenker-Ravi E, Lambert L, Vincent-Delorme C, et al. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy. Hum Mutat. 2020;41:2167–78.

    PubMed  Google Scholar 

  25. McDermott JH, Study DD, Clayton-Smith J. Sibling recurrence of total anomalous pulmonary venous drainage. Eur J Med Genet. 2017;60:265–7.

    CAS  PubMed  Google Scholar 

  26. Cheng H, Dharmadhikari AV, Varland S, Ma N, Domingo D, Kleyner R, et al. Truncating variants in NAA15 are associated with variable levels of intellectual disability, autism spectrum disorder, and congenital anomalies. Am J Hum Genet. 2018;102:985–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fick TA, Scott DA, Lupo PJ, Weigand J, Morris SA. The frequency and efficacy of genetic testing in individuals with scimitar syndrome. Cardiol Young-. 2022;32:550–7.

    PubMed  Google Scholar 

  28. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 2015;350:1262–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013;498:220–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Thorwarth A, Schnittert-Hubener S, Schrumpf P, Muller I, Jyrch S, Dame C, et al. Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. J Med Genet. 2014;51:375–87.

    CAS  PubMed  Google Scholar 

  31. Hayasaka I, Cho K, Akimoto T, Ikeda M, Uzuki Y, Yamada M, et al. Genetic basis for childhood interstitial lung disease among Japanese infants and children. Pediatr Res. 2018;83:477–83.

    CAS  PubMed  Google Scholar 

  32. Li X, Shi G, Li Y, Zhang X, Xiang Y, Wang T, et al. 15q11.2 deletion is enriched in patients with total anomalous pulmonary venous connection. Journal of medical genetics. 2020.

  33. Kuroda Y, Ohashi I, Naruto T, Ida K, Enomoto Y, Saito T, et al. Familial total anomalous pulmonary venous return with 15q11.2 (BP1-BP2) microdeletion. J Hum Genet. 2018;63:1185–8.

    CAS  PubMed  Google Scholar 

  34. Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, et al. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015;58:140–7.

    PubMed  Google Scholar 

  35. Meerschaut I, Vergult S, Dheedene A, Menten B, De Groote K, De, et al. A reassessment of copy number variations in congenital heart defects: picturing the whole genome. Genes (Basel). 2021;12:1048.

    CAS  PubMed  Google Scholar 

  36. Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, Verschuuren-Bemelmans CC, et al. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002;39:876–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Rosenfeld JA, Traylor RN, Schaefer GB, McPherson EW, Ballif BC, Klopocki E, et al. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes. Eur J Hum. Gene 2012;20:754–61.

    CAS  Google Scholar 

  38. Liu C, Cao R, Xu Y, Li T, Li F, Chen S, et al. Rare copy number variants analysis identifies novel candidate genes in heterotaxy syndrome patients with congenital heart defects. Genome Med. 2018;10:40.

    PubMed  PubMed Central  Google Scholar 

  39. Mohun T, Adams DJ, Baldock R, Bhattacharya S, Copp AJ, Hemberger M, et al. Deciphering the mechanisms of developmental disorders (DMDD): a new programme for phenotyping embryonic lethal mice. Dis Model Mech. 2013;6:562–6.

    PubMed  PubMed Central  Google Scholar 

  40. Rump P, de Leeuw N, van Essen AJ, Verschuuren-Bemelmans CC, Veenstra-Knol HE, Swinkels ME, et al. Central 22q11.2 deletions. Am J Med Genet A 2014;164A:2707–23.

    PubMed  Google Scholar 

  41. Faurschou S, Lildballe DL, Maroun LL, Helvind M, Rasmussen M. Total anomalous pulmonary venous connection in mother and son with a Central 22q11.2 microdeletion. Case Rep. Genet. 2021;2021:5539855.

    PubMed  PubMed Central  Google Scholar 

  42. Breckpot J, Thienpont B, Bauters M, Tranchevent LC, Gewillig M, Allegaert K, et al. Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1. Am J Med Genet A 2012;158A:574–80.

    PubMed  Google Scholar 

  43. Racedo SE, McDonald-McGinn DM, Chung JH, Goldmuntz E, Zackai E, Emanuel BS, et al. Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation. Am J Hum Genet. 2015;96:235–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet. 2001;27:293–8.

    CAS  PubMed  Google Scholar 

  45. Lehalle D, Gordon CT, Oufadem M, Goudefroye G, Boutaud L, Alessandri JL, et al. Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients. Hum Mutat. 2014;35:478–85.

    CAS  PubMed  Google Scholar 

  46. Panizzi JR, Becker-Heck A, Castleman VH, Al-Mutairi DA, Liu Y, Loges NT, et al. CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet. 2012;44:714–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Postma AV, van Engelen K, van de Meerakker J, Rahman T, Probst S, Baars MJ, et al. Mutations in the sarcomere gene MYH7 in Ebstein anomaly. Circ Cardiovasc Genet. 2011;4:43–50.

    CAS  PubMed  Google Scholar 

  48. Chirita Emandi A, Dobrescu AI, Doros G, Hyon C, Miclea D, Popoiu C, et al. A novel 3q29 deletion in association with developmental delay and heart malformation-case report with literature review. Front Pediatr. 2019;7:270.

    PubMed  PubMed Central  Google Scholar 

  49. Tomita-Mitchell A, Mahnke DK, Struble CA, Tuffnell ME, Stamm KD, Hidestrand M, et al. Human gene copy number spectra analysis in congenital heart malformations. Physiol Genomics. 2012;44:518–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nagamani SC, Erez A, Bader P, Lalani SR, Scott DA, Scaglia F, et al. Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet. 2011;19:280–6.

    PubMed  Google Scholar 

  51. Monteiro RAC, de Freitas ML, Vianna GS, de Oliveira VT, Pietra RX, Ferreira LCA, et al. Major contribution of genomic copy number variation in syndromic congenital heart disease: the use of MLPA as the first genetic test. Mol Syndromol. 2017;8:227–35.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from contact@deciphergenomics.org. We note that those who carried out the original analysis and collection of the DECIPHER data bear no responsibility for the further analysis or interpretation of the data.

Funding

This work was supported, in part, by National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01HD098458 to DAS. The CCVM Registry is supported in part by American Heart Association Transformational Award AHA 19TPA34850054 (SMW). Funding for the DECIPHER project was provided by Wellcome.

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Emily A. Huth, Xiaonan Zhao, Nichole Owen, Pamela N. Luna, Chad A. Shaw, Seema R. Lalani, Jill A. Rosenfeld & Daryl A. Scott

  2. Baylor Genetics, Houston, TX, USA

    Xiaonan Zhao & Nichole Owen

  3. Department of Clinical Medicine, Aarhus University, 8000, Aarhus, C, Denmark

    Ida Vogel

  4. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

    Inger L. H. Dorf

  5. West of Scotland Genomics Service, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK

    Shelagh Joss

  6. Manchester Centre For Genomic Medicine, Manchester University Hospitals, Manchester, M13 9WL, UK

    Jill Clayton-Smith

  7. University of Manchester, Manchester, M13 9PL, UK

    Jill Clayton-Smith

  8. Department of Clinical Genetics, Sheffield, Children’s Hospital, UK

    Michael J. Parker

  9. Pediatric Cardiology Maastricht University Medical Centre, Maastricht, The Netherlands

    Jacoba J. Louw

  10. Department of Cardiovascular Sciences KU Leuven, Leuven, Belgium

    Marc Gewillig

  11. Pediatric Cardiology University Hospitals Leuven, Leuven, Belgium

    Marc Gewillig

  12. Center for Human Genetics, University Hospitals Leuven, Catholic University, Leuven, Belgium

    Jeroen Breckpot

  13. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, LS7 4SA, UK

    Alison Kraus

  14. Oxford Centre for Genomic Medicine, Oxford University Hospital, Oxford, OX3 7HE, UK

    Erina Sasaki & Usha Kini

  15. Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK

    Usha Kini

  16. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia

    Trent Burgess & Tiong Y. Tan

  17. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    Trent Burgess & Tiong Y. Tan

  18. East Anglian Medical Genetics Service, Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

    Ruth Armstrong

  19. Genetic Health Service NZ, Wellington, New Zealand

    Katherine Neas

  20. Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy

    Giovanni B. Ferrero

  21. Department of Medical Sciences, University of Torino, Torino, Italy

    Alfredo Brusco

  22. Città della Salute e della Scienza University Hospital, Torino, Italy

    Alfredo Brusco

  23. Department Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Wihelmina S. Kerstjens-Frederikse

  24. Peninsula Clinical Genetics Service, Exeter, UK

    Julia Rankin

  25. Indiana University School of Medicine, Indianapolis, IN, USA

    Lindsey R. Helvaty & Benjamin J. Landis

  26. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Gabrielle C. Geddes & Stephanie M. Ware

  27. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Gabrielle C. Geddes & Stephanie M. Ware

  28. Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada

    Kim L. McBride

  29. Center for Cardiovascular Research, Nationwide Children’s Hospital, Columbus, OH, USA

    Kim L. McBride

  30. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA

    Daryl A. Scott

Authors
  1. Emily A. Huth
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  2. Xiaonan Zhao
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  19. Katherine Neas
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  30. Seema R. Lalani
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  32. Daryl A. Scott
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Contributions

DAS conceived the study. EAH wrote the first draft of the manuscript. CAS and PNL were responsible for the machine learning. XZ and NO were responsible for providing updated SNV and CNV variant interpretations, respectively, based on ACMG criteria. IV, ILHD, SJ, JC-S, MJP, JJL, MG, JB, AK, ES, UK, TB, TYT, RA, KN, GBF, AB, WSK-F, JR, LRH, BJL, GCG, KLM, SMW, and SRL obtained and provided clinical and molecular data. EAH and DAS analyzed clinical and molecular data. All authors reviewed, edited, and approved the final draft.

Corresponding author

Correspondence to Daryl A. Scott.

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Competing interests

The Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics.

Ethical approval

This study was approved by the institutional review board of Baylor College of Medicine (protocol H-47546) and was conducted in accordance with the ethical standards of this institution’s committee on human research and international standards.

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Huth, E.A., Zhao, X., Owen, N. et al. Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return. Eur J Hum Genet 31, 1430–1439 (2023). https://doi.org/10.1038/s41431-023-01451-4

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