Sarah Boissel1, Catherine Fallet-Bianco1,2, David Chitayat3, Valérie Kremer4, Christina Nassif1, Françoise Rypens1,5, Marie-Ange Delrue1,6, Dorothée Dal Soglio1,2, Luc L Oligny1,2, Natalie Patey1,2, Elisabeth Flori4, Mireille Cloutier7, David Dyment7, Philippe Campeau1,6, Aspasia Karalis1,6, Sonia Nizard1,6, William D Fraser8, François Audibert1,9, Emmanuelle Lemyre1,6, Guy A Rouleau10, Fadi F Hamdan1, Zoha Kibar1,11, Jacques L Michaud12,13. 1. CHU Sainte-Justine, Montreal, Quebec, Canada. 2. Department of Pathology, Université de Montréal, Montreal, Quebec, Canada. 3. The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Canada, Ontario. 4. Department of Cytogenetics, Strasbourg University Hospital, Strasbourg, France. 5. Department of Radiology, Radio-oncology and Nuclear Medicine, Université de Montréal, Montreal, Quebec, Canada. 6. Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada. 7. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada. 8. Research Center, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada. 9. Department of Obstetrics and Gynecology, Université de Montréal, Montreal, Quebec, Canada. 10. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. 11. Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada. 12. CHU Sainte-Justine, Montreal, Quebec, Canada. jacques.michaud@recherche-ste-justine.qc.ca. 13. Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada. jacques.michaud@recherche-ste-justine.qc.ca.
Abstract
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 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. 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.
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 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. 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.
Authors: Isabelle Schrauwen; Elina Kari; Jacob Mattox; Lorida Llaci; Joanna Smeeton; Marcus Naymik; David W Raible; James A Knowles; J Gage Crump; Matthew J Huentelman; Rick A Friedman Journal: Hum Genet Date: 2018-06-28 Impact factor: 4.132
Authors: F Mone; R Y Eberhardt; M E Hurles; D J Mcmullan; E R Maher; J Lord; L S Chitty; E Dempsey; T Homfray; J L Giordano; R J Wapner; L Sun; T N Sparks; M E Norton; M D Kilby Journal: Ultrasound Obstet Gynecol Date: 2021-10 Impact factor: 8.678
Authors: Elizabeth A Normand; Alicia Braxton; Salma Nassef; Patricia A Ward; Francesco Vetrini; Weimin He; Vipulkumar Patel; Chunjing Qu; Lauren E Westerfield; Samantha Stover; Avinash V Dharmadhikari; Donna M Muzny; Richard A Gibbs; Hongzheng Dai; Linyan Meng; Xia Wang; Rui Xiao; Pengfei Liu; Weimin Bi; Fan Xia; Magdalena Walkiewicz; Ignatia B Van den Veyver; Christine M Eng; Yaping Yang Journal: Genome Med Date: 2018-09-28 Impact factor: 11.117