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Original article
Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders
  1. Victor Murcia Pienkowski1,2,
  2. Marzena Kucharczyk3,
  3. Marlena Młynek3,
  4. Krzysztof Szczałuba1,
  5. Małgorzata Rydzanicz1,
  6. Barbara Poszewiecka4,
  7. Agata Skórka3,5,
  8. Maciej Sykulski1,6,
  9. Anna Biernacka1,2,
  10. Agnieszka Anna Koppolu1,2,
  11. Renata Posmyk7,8,
  12. Anna Walczak1,
  13. Joanna Kosińska1,
  14. Paweł Krajewski9,
  15. Jennifer Castaneda10,
  16. Ewa Obersztyn10,
  17. Elżbieta Jurkiewicz11,
  18. Robert Śmigiel12,
  19. Anna Gambin4,
  20. Krystyna Chrzanowska3,
  21. Małgorzata Krajewska-Walasek3,
  22. Rafał Płoski1
  1. 1Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
  2. 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
  3. 3Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland
  4. 4Faculty of Mathematics, Informatics and Mechanics, Institute of Informatics, University of Warsaw, Warsaw, Poland
  5. 5Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland
  6. 6genXone, Poznan, Poland
  7. 7Department of Clinical Genetics, Podlaskie Medical Center, Bialystok, Poland
  8. 8Department of Perinatology, Medical University of Bialystok, Bialystok, Poland
  9. 9Department of Forensic Medicine, Medical University of Warsaw, Warsaw, Poland
  10. 10Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
  11. 11Department of Diagnostic Imaging, The Children’s Memorial Health Institute, Warsaw, Poland
  12. 12Department of Pediatrics and Rare Disorder, Wroclaw Medical University, Wroclaw, Poland
  1. Correspondence to Professor Rafał Płoski, Department of Medical Genetics, Medical University of Warsaw, Warsaw 02-106, Poland; rploski{at}


Background Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients.

Methods Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts.

Results In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter.

Conclusion SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene–disease associations.

  • EFNA5
  • BAHD1
  • PPP2R5E
  • next-generation sequencing
  • de novo balanced translocations

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  • VMP, MK and MM contributed equally.

  • Contributors VMP, KS, RPo, RPl, MKW, RS, AG, JC, BP and AS wrote the manuscript. VMP, MK and MM performed the experiments. RPl, MR, AG, KC and MKW designed the experiment. VMP, MK and MM designed the pipeline. VMP, BP, AG and MS performed bioinformatic analysis. MM, MK, AS, RPo, PK, JC, EW, RS, KC and MKW contacted the patients. VMP, MR, AAK, AB, AW and JK performed next-generation sequencing. EJ preformed MRI analysis.

  • Funding The research was supported by the National Science Centre (NCN) grant number 2016/21/B/NZ5/02541.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Ethics approval for the study was granted by the Ethical Committee at the Medical University of Warsaw (KB/127/2017).

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

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