TY - JOUR T1 - Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations JF - Journal of Medical Genetics JO - J Med Genet SP - 400 LP - 413 DO - 10.1136/jmedgenet-2020-106867 VL - 58 IS - 6 AU - Mathilde Lefebvre AU - Ange-Line Bruel AU - Emilie Tisserant AU - Nicolas Bourgon AU - Yannis Duffourd AU - Sophie Collardeau-Frachon AU - Tania Attie-Bitach AU - Paul Kuentz AU - Mirna assoum AU - Elise Schaefer AU - Salima El Chehadeh AU - Maria Cristina Antal AU - Valérie Kremer AU - Françoise Girard-Lemaitre AU - Jean-Louis Mandel AU - Daphne Lehalle AU - Sophie Nambot AU - Nolwenn Jean-Marçais AU - Nada Houcinat AU - Sébastien Moutton AU - Nathalie Marle AU - Laetita Lambert AU - Philippe Jonveaux AU - Bernard Foliguet AU - Jean-Pierre Mazutti AU - Dominique Gaillard AU - Elisabeth Alanio AU - Celine Poirisier AU - Anne-Sophie Lebre AU - Marion Aubert-Lenoir AU - Francine Arbez-Gindre AU - Sylvie Odent AU - Chloé Quélin AU - Philippe Loget AU - Melanie Fradin AU - Marjolaine Willems AU - Nicole Bigi AU - Marie-José Perez AU - Sophie Blesson AU - Christine Francannet AU - Anne-Marie Beaufrere AU - Sophie Patrier-Sallebert AU - Anne-Marie Guerrot AU - Alice Goldenberg AU - Anne-Claire Brehin AU - James Lespinasse AU - Renaud Touraine AU - Yline Capri AU - Marie-Hélène Saint-Frison AU - Nicole Laurent AU - Christophe Philippe AU - Frederic Tran Mau-them AU - Julien Thevenon AU - Laurence Faivre AU - Christel Thauvin-Robinet AU - Antonio Vitobello Y1 - 2021/06/01 UR - http://jmg.bmj.com/content/58/6/400.abstract N2 - Purpose Molecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.Methods We performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.Results sES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).Conclusions This method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.All data relevant to the study are included in the article or uploaded as supplementary information. ER -