Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis

被引:67
作者
Boissel, Sarah [1 ]
Fallet-Bianco, Catherine [1 ,2 ]
Chitayat, David [3 ]
Kremer, Valerie [4 ]
Nassif, Christina [1 ]
Rypens, Francoise [1 ,5 ]
Delrue, Marie-Ange [1 ,6 ]
Dal Soglio, Dorothee [1 ,2 ]
Oligny, Luc L. [1 ,2 ]
Patey, Natalie [1 ,2 ]
Flori, Elisabeth [4 ]
Cloutier, Mireille [7 ]
Dyment, David [7 ]
Campeau, Philippe [1 ,6 ]
Karalis, Aspasia [1 ,6 ]
Nizard, Sonia [1 ,6 ]
Fraser, William D. [8 ]
Audibert, Francois [1 ,9 ]
Lemyre, Emmanuelle [1 ,6 ]
Rouleau, Guy A. [10 ]
Hamdan, Fadi F. [1 ]
Kibar, Zoha [1 ,11 ]
Michaud, Jacques L. [1 ,11 ]
机构
[1] CHU St Justine, Montreal, PQ, Canada
[2] Univ Montreal, Dept Pathol, Montreal, PQ, Canada
[3] Mt Sinai Hosp, Prenatal Diag & Med Genet Program, Toronto, ON, Canada
[4] Strasbourg Univ Hosp, Dept Cytogenet, Strasbourg, France
[5] Univ Montreal, Dept Radiol Radiooncol & Nucl Med, Montreal, PQ, Canada
[6] Univ Montreal, Dept Pediat, Montreal, PQ, Canada
[7] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON, Canada
[8] Ctr Hosp Univ Sherbrooke, Res Ctr, Sherbrooke, PQ, Canada
[9] Univ Montreal, Dept Obstet & Gynecol, Montreal, PQ, Canada
[10] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada
[11] Univ Montreal, Dept Neurosci, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
birth defects; de novo mutations; exome sequencing; fetal anomalies; GREB1L; PRENATAL-DIAGNOSIS; SPECTRUM; HYDROCEPHALUS; DYSFUNCTION; LETHALITY; DOMINANT; DISTINCT; DEFECTS; REVEALS; DISEASE;
D O I
10.1038/gim.2017.173
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Purpose: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. Methods: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal agenesis or dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. Results: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. Conclusion: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power -but also the challenges-of WES in prenatal diagnosis.
引用
收藏
页码:745 / 753
页数:9
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