Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140 - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Human Mutation Année : 2018

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

Isabelle Perrault
  • Fonction : Auteur
Marion Delbarre
  • Fonction : Auteur
Manuela Antin
  • Fonction : Auteur
Anne-Sophie Leuvrey
  • Fonction : Auteur
Charline Henry
  • Fonction : Auteur
  • PersonId : 1019495
Hélène Blanché
Eva Decker
  • Fonction : Auteur
Katja Kloth
  • Fonction : Auteur
Günter Klaus
  • Fonction : Auteur
Christoph Mache
  • Fonction : Auteur
Dominique Martin-Coignard
  • Fonction : Auteur
Steven Mcginn
  • Fonction : Auteur
Anne Boland
Jean-François Deleuze
Sophie Saunier
  • Fonction : Auteur
Jean-Michel Rozet
  • Fonction : Auteur
Carsten Bergmann
  • Fonction : Auteur

Résumé

Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.

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Génétique
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Dates et versions

hal-02371583 , version 1 (19-11-2019)

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Véronique Geoffroy, Corinne Stoetzel, Sophie Scheidecker, Elise Schaefer, Isabelle Perrault, et al.. Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140. Human Mutation, 2018, 39 (7), pp.983-992. ⟨10.1002/humu.23539⟩. ⟨hal-02371583⟩
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