CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability

Louise Montagne, Mehdi Derhourhi, Amélie Piton, Bénédicte Toussaint, Emmanuelle Durand, Emmanuel Vaillant, Dorothée Thuillier, Stefan Gaget, Franck De Graeve, Iandry Rabearivelo, Amélie Lansiaux, Bruno Lenne, Sylvie Sukno, Rachel Desailloud, Miriam Cnop, Ramona Nicolescu, Lior Cohen, Jean François Zagury, Mélanie Amouyal, Jacques WeillJean Muller, Olivier Sand, Bruno Delobel, Philippe Froguel, Amélie Bonnefond

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Objective: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. Methods: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (n total = 145). Results: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. Conclusions: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalMolecular Metabolism
Volume13
DOIs
StatePublished - 1 Jul 2018
Externally publishedYes

Keywords

  • Augmented whole-exome sequencing
  • Copy number variation
  • Intellectual disability
  • Molecular diagnosis
  • Next-generation sequencing
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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