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Article Dans Une Revue Journal of Medical Genetics Année : 2021

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

1 CIC Nantes - Centre d’Investigation Clinique de Nantes
2 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
3 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
4 HCL - Hospices Civils de Lyon
5 Hôpital Necker - Enfants Malades [AP-HP]
6 Equipe GAD (LNC - U1231)
7 Laboratoire de Diagnostic Génétique [CHU Strasbourg]
8 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
9 Hôpital de Hautepierre [Strasbourg]
10 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
11 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
12 CERN - European Organization for Nuclear Research
13 Service de Génétique [CHRU Nancy]
14 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
15 Hôpital universitaire Robert Debré [Reims]
16 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
17 Service d'Anatomie pathologique [CHRU Besançon]
18 IGDR - Institut de Génétique et Développement de Rennes
19 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
20 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
21 CHU - Hôpital Lapeyronie [Montpellier]
22 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
23 IBHGC - Institut de Biomécanique Humaine Georges Charpak
24 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
25 Service de Génétique Médicale [CHU Clermont-Ferrand]
26 CHU Estaing [Clermont-Ferrand]
27 CHU Rouen
28 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
29 Centre Hospitalier Métropole Savoie [Chambéry]
30 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
31 Département de génétique [Robert Debré]
32 Hôpital Robert Debré
33 Plateau technique de Biologie [CHU de Dijon]
34 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
S. Patrier-Sallebert
  • Fonction : Auteur

Résumé

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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Dates et versions

inserm-03231676 , version 1 (21-05-2021)

Identifiants

Citer

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, 2021, 58 (6), pp.400-413. ⟨10.1136/jmedgenet-2020-106867⟩. ⟨inserm-03231676⟩
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