%0 Journal Article
%T Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140.
%A Geoffroy V
%A Stoetzel C
%A Scheidecker S
%A Schaefer E
%A Perrault I
%A Bär S
%A Kröll A
%A Delbarre M
%A Antin M
%A Leuvrey AS
%A Henry C
%A Blanché H
%A Decker E
%A Kloth K
%A Klaus G
%A Mache C
%A Martin-Coignard D
%A McGinn S
%A Boland A
%A Deleuze JF
%A Friant S
%A Saunier S
%A Rozet JM
%A Bergmann C
%A Dollfus H
%A Muller J
%J Hum Mutat
%V 39
%N 7
%D 07 2018
%M 29688594
%F 4.7
%R 10.1002/humu.23539
%X 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.