Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140
Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140
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DOI：
10.1002/humu.23539
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发表时间：
2018-07-01
期刊：
影响因子：
3.9
通讯作者：
Muller, Jean
中科院分区：
文献类型：
--
作者：
Geoffroy, Veronique;Stoetzel, Corinne;Muller, Jean
纤毛病是一种广泛的罕见疾病，具有重叠的表型和高度的遗传异质性。其中，IFFT 140涉及从孤立的色素性视网膜到更多综合征病例的各种表型。通过对未确诊的纤毛病患者进行全基因组测序，我们在IFFT 140中发现了一个新的外显子27-30（6.7kb）的重复串联重复，c.3454-488_4182+ 2588 dup p。（Tyr1152_Thr1394dup），全外显子组测序缺失。在患者的皮肤成纤维细胞上评估突变的致病性。筛选了数百例纤毛病变表型患者，并在11个家族中鉴定了双等位基因突变，代表12种致病性变体，其中7种是新的。在那些不相关的家庭，特别是与Mainzer-Saldino综合征，8进行了相同的串联重复（两个在纯合子状态和杂合子状态六）。总之，我们证明了IFFT 140相关疾病中结构变异的意义，扩大了其突变谱。我们还提供了一个独特的基因组事件介导的一个共同的单倍型上发生的α-Alu重组的证据。我们证实，全基因组测序可以在检测基因组疾病的结构变异的能力。
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 (6.7kb) 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.