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

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.