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.
- molecular genetics
- reproductive medicine
- complex traits
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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CT-R and AV are joint senior authors.
ML and A-LB are joint first authors.
ML and A-LB contributed equally.
Contributors ML performed some autopsy, analysed exome data, shared part of the data, wrote and submitted the manuscript. ALB analysed exome date and shared part of the data. AV and CTR co-directed the work.ET and YD performed bioinformatics analysis. NBo, PK, MA, CP, FTMT and JT analysed exome data. SCF and TAB gave expert advice on fetal phenotypes. MCA, BF, JPM, DG, FAG, EA, CQ, PL, NBi, MJP, SB, AMB, SP, ACB, MHS and NL performed the autopsy and gave frozen tissue. ES, SEC, DL, SN, NJM, NH, SM, LL, MAL, SO, MF, MW, CQ, CF, AMG, AG, JL, RT, YC and LF followed the patient, prescribed genetics investigation and gave patient data. VK, FGL, JLM, NM, PJ, CP and ASL performed cytogenetics test. CT-R and AV are last authors.
Funding This study was funded by Interregional French PHRC Interregional 14-013 FOETEX.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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