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




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.


We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/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.


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.


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.

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This work was supported by grants from the Canadian Institutes of Health Research (CRI 88413 and MOP-136913) and the Fonds de la Recherche du Québec-Santé, as part of the research programs of the Integrated Research Network in Perinatology of Quebec and Eastern Ontario and Réseau de Génétique Médicale Appliquée du Québec. We are grateful to the bioinformatic analysis team of the Réseau de Génétique Médicale Appliquée du Québec (Dan Spiegelman, Ousmane Diallo, Edouard Henrion, Alexandre Dionne-Laporte) for the primary analysis of the sequence data.

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The authors declare no conflict of interest.

Correspondence to Jacques L Michaud MD.

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