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Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations
  1. Caroline Schluth-Bolard1,2,
  2. Audrey Labalme1,
  3. Marie-Pierre Cordier1,
  4. Marianne Till1,
  5. Gwenaël Nadeau3,
  6. Hélène Tevissen4,
  7. Gaétan Lesca1,2,
  8. Nadia Boutry-Kryza2,5,
  9. Sylvie Rossignol6,7,
  10. Delphine Rocas1,
  11. Estelle Dubruc1,
  12. Patrick Edery1,2,
  13. Damien Sanlaville1,2
  1. 1Laboratoire de Cytogénétique Constitutionnelle, Service de Génétique, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France
  2. 2Equipe TIGER, INSERM U1028, CNRS UMR5292, Université Claude Bernard Lyon 1, Lyon, France
  3. 3Centre Hospitalier de Valence, Unité Fonctionnelle de Cytogénétique, Valence, France
  4. 4Centre Hospitalier de Valence, Service de Pédiatrie, Valence, France
  5. 5Laboratoire de Génétique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
  6. 6Explorations Fonctionnelles Endocriniennes, APHP, Hôpital Armand Trousseau, Paris, France
  7. 7INSERM, UMRS U938, Paris, France
  1. Correspondence to Dr Caroline Schluth-Bolard, Laboratoire de Cytogénétique Constitutionnelle, Service de Génétique, Centre de Biologie et de Pathologie Est, 59, boulevard Pinel, BRON 69677 Cedex, France; caroline.schluth-bolard{at}


Background Apparently balanced chromosomal rearrangements (ABCR) are associated with an abnormal phenotype in 6% of cases. This may be due to cryptic genomic imbalances or to the disruption of genes at the breakpoint. However, breakpoint cloning using conventional methods (ie, fluorescent in situ hybridisation (FISH), Southern blot) is often laborious and time consuming. In this work, we used next generation sequencing (NGS) to locate breakpoints at the molecular level in four patients with multiple congenital abnormalities and/or intellectual deficiency (MCA/ID) who were carrying ABCR (one translocation, one complex chromosomal rearrangement and two inversions), which corresponded to nine breakpoints.

Methods Genomic imbalance was previously excluded by array comparative genomic hybridisation (CGH) in all four patients. Whole genome paired-end protocol was used to identify breakpoints. The results were verified by FISH and by PCR with Sanger sequencing.

Results We were able to map all nine breakpoints. NGS revealed an additional breakpoint due to a cryptic inversion at a breakpoint junction in one patient. Nine of 10 breakpoints occurred in repetitive elements and five genes were disrupted in their intronic sequence (TCF4, SHANK2, PPFIA1, RAB19, KCNQ1).

Conclusions NGS is a powerful tool allowing rapid breakpoint cloning of ABCR at the molecular level. We showed that in three out of four patients, gene disruption could account for the phenotype, allowing adapted genetic counselling and stopping unnecessary investigations. We propose that patients carrying ABCR with an abnormal phenotype should be explored systematically by NGS once a genomic imbalance has been excluded by array CGH.

  • Next Generation Sequencing
  • Chromosome rearrangement
  • Breakpoint
  • Intellectual deficiency
  • Malformations

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