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Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

M. Lefebvre 1 A. L. Bruel 2, 3 E. Tisserant 3 N. Bourgon 3 Y. Duffourd 3, 2 S. Collardeau-Frachon 4 T. Attie-Bitach 5 P. Kuentz 6 M. Assoum 3 E. Schaefer 7 S. El Chehadeh 8 M. C. Antal 9 V. Kremer 8 F. Girard-Lemaitre 10 J. L. Mandel 10 D. Lehalle 2, 3 S. Nambot 2, 3 N. Jean-Marcais 2 N. Houcinat 2, 3 S. Moutton 2, 3 N. Marle 2, 11 L. Lambert 12 P. Jonveaux 13 B. Foliguet 14 J. P. Mazutti 14 D. Gaillard 15 E. Alanio 15 C. Poirisier 15 A. S. Lebre 15 M. Aubert-Lenoir 16 F. Arbez-Gindre 17 S. Odent 18 C. Quelin 19 P. Loget 20 M. Fradin 18, 20 M. Willems 21 N. Bigi 22 M. J. Perez 23 S. Blesson 24 C. Francannet 25 A. M. Beaufrere 26 S. Patrier-Sallebert 27 A. M. Guerrot 27, 28 A. Goldenberg 28, 27 A. C. Brehin 27, 28 J. Lespinasse 29 R. Touraine 30 Y. Capri 31 M. H. Saint-Frison 32 N. Laurent 2 C. Philippe 3, 2 F. Tran Mau-Them 6, 33 J. Thevenon 34 L. Faivre 3, 2 C. Thauvin-Robinet 3, 2 A. Vitobello 2, 3 
6 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
Abstract : 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.
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Submitted on : Friday, May 21, 2021 - 9:33:25 AM
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M. Lefebvre, A. L. Bruel, E. Tisserant, N. Bourgon, Y. Duffourd, et al.. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations. Journal of Medical Genetics, BMJ Publishing Group, 2021, 58 (6), pp.400-413. ⟨10.1136/jmedgenet-2020-106867⟩. ⟨inserm-03231676⟩



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