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

Hum Mutat. 2018 Jul;39(7):983-992. doi: 10.1002/humu.23539. Epub 2018 May 8.


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.

Keywords: Alu-mediated recombination; IFT140; Mainzer-Saldino syndrome; copy number variation; structural variation; tandem duplication; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements / genetics
  • Carrier Proteins / genetics*
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Ciliopathies / genetics*
  • Ciliopathies / pathology
  • Databases, Genetic
  • Exons / genetics
  • Female
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology
  • Whole Genome Sequencing*


  • Carrier Proteins
  • IFT140 protein, human

Supplementary concepts

  • Mainzer-Saldino Disease