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Original research
Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects
  1. Yoav Bolkier1,2,3,
  2. Ortal Barel4,5,
  3. Dina Marek-Yagel2,3,
  4. Danit Atias-Varon6,
  5. Maayan Kagan2,6,
  6. Amir Vardi2,7,
  7. David Mishali2,8,
  8. Uriel Katz1,2,
  9. Yishay Salem1,2,
  10. Tal Tirosh-Wagner1,2,
  11. Jeffrey M Jacobson2,9,
  12. Annick Raas-Rothschild2,10,
  13. Odelia Chorin2,10,
  14. Aviva Eliyahu2,11,
  15. Yarden Sarouf2,12,
  16. Omer Shlomovitz2,12,
  17. Alvit Veber3,
  18. Nechama Shalva3,
  19. Elisheva Javasky4,
  20. Yishay Ben Moshe2,12,
  21. Orna Staretz-Chacham13,
  22. Gideon Rechavi2,5,14,
  23. Shrikant Mane15,
  24. Yair Anikster2,3,5,
  25. Asaf Vivante2,12,16,
  26. Ben Pode-Shakked2,3,12,16
  1. 1Pediatric Heart Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  2. 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  3. 3Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  4. 4Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel
  5. 5The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel
  6. 6Pediatric Nephrology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  7. 7Department of Pediatric Cardiac Intensive Care, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  8. 8Department of Pediatric Cardiac Intensive Care, Edmond Safra International Congenital Heart Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  9. 9Pediatric Imaging Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  10. 10The Institute of Rare Diseases, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  11. 11The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
  12. 12Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
  13. 13Metabolic Clinic, Division of Pediatrics, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel
  14. 14Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel
  15. 15Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
  16. 16Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, Israel
  1. Correspondence to Dr Ben Pode-Shakked, Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel; ben_pode{at}hotmail.com

Abstract

Background The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left–right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.

Objective We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab–Muslim descent, using next-generation sequencing techniques.

Methods Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.

Results Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46.

Conclusions Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

  • congenital
  • Hereditary
  • and neonatal diseases and abnormalities
  • heart defects
  • congenital

Data availability statement

Data are available upon reasonable request from the corresponding author.

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Data availability statement

Data are available upon reasonable request from the corresponding author.

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Footnotes

  • AV and BP-S are joint senior authors.

  • YB, OB and DM-Y contributed equally.

  • Contributors BP-S, YB, YA and AVi initiated the study and substantially contributed to its conception and design, acquisition, analysis and interpretation of the data, and wrote the manuscript. MK, AVa, DM, UK, YS, TT-W, JMJ, AR, OC, AE, YS, OS, AVe, NS, YBM, OS-C, YA and BP-S contributed to the recruitment of patients and acquisition of data. OB, DM-Y, DA-V, EJ, GR and SM contributed to the WES data analysis and interpretation. In addition, all authors critically reviewed the manuscript and approved the submitted version.

  • Funding The Yale Center for Mendelian Genomics (NIH M#UM1HG006504) is funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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