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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.

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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 All previously unpublished variants from the BG clinical database and the CCVM database have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/; SNVs =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).

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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

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  1. Emily A. Huth
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  2. Xiaonan Zhao
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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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