Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts

Abstract

We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. Results: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. Conclusion: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.

Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses

“…By ES detection, the diagnostic rate in the retrospective cohort (17.3%) was higher than that in the prospective cohort (12.4%). Similar results were obtained in the most recent study comparing prospective (13%, 24/183) and retrospective (29%, 35/120) cohorts of fetal clinical exome sequencing [13]. As ES was performed at the end of the pregnancy in the retrospective cohort, fetal phenotype observation was much more distinct and comprehensive.…”

“…Given the success in postnatal patient populations and the limitations of current genetic testing for prenatal cases, ES is now applied to prenatal diagnosis (pES) more widely. There have been several reports on the application of ES in prenatal diagnosis in relatively large sample sizes (n>100) [7][8][9][10][11][12][13], with diagnostic rates ranging from 8.5 to 35% [14]. However, data on integrating ES into clinical practice and returning results during pregnancy remain limited.…”

KMT2A‐D pathogenicity, prevalence, and variation according to a population database

“…Both c.7411C > T and c.2994del along with two other KMT2D variants identified as pathogenic and likely pathogenic by ACMG criteria (c.4168dup, p.A1390GfsTer42 and c.10180C > T, p.Gln3394Ter) have been reported to be de novo in individuals affected with Kabuki syndrome. 29 , 42 , 43 , 44 , 45 , 46 Given the autosomal dominant inheritance pattern, this brings into question why damaging germline variants would be present among individuals or any first‐degree relative screened for severe pediatric disease within the gnomAD database. 46 Penetrance is considered nearly complete for KMT2D ; therefore, it is likely these individuals may have mosaic Kabuki, which has been found in two studies to result in individuals that are mildly/minimally affected.…”

“…Five variants identified as pathogenic by both approaches included one KMT2A frameshift variant (c.134del, p.Pro45ArgfsTer105) as well as three KMT2D frameshifts (c.15953_15956del, p.Leu5318SerfsTer14; c.4168dup, p.Ala1390GlyfsTer42; and c.2994del, p.Met999Ter) and one nonsense (c.7411C > T, p.Arg2471Ter). Both c.7411C > T and c.2994del along with two other KMT2D variants identified as pathogenic and likely pathogenic by ACMG criteria (c.4168dup, p.A1390GfsTer42 and c.10180C > T, p.Gln3394Ter) have been reported to be de novo in individuals affected with Kabuki syndrome 29,42–46 . Given the autosomal dominant inheritance pattern, this brings into question why damaging germline variants would be present among individuals or any first‐degree relative screened for severe pediatric disease within the gnomAD database 46 .…”

Utility of trio‐based prenatal exome sequencing incorporating splice‐site and mitochondrial genome assessment in pregnancies with fetal ultrasound anomalies: prospective cohort study

“…The diagnostic yield of ES was lower (8-10%) in unselected prospective cohorts 14,15 and higher (> 40%) in small and selected cohorts of fetuses 16,17 . This variation may be attributable not only to different study selection criteria, but also to the test strategy used (trio-based or proband-only) and different panels of genes included in the analysis process, such as developmental disorder genes in the PAGE study 14,15 and coding exons of genes associated with Mendelian disorders (clinical exome sequencing) in the study by Marangoni et al 18 . However, none of these studies involved testing of mitochondrial genomes by prenatal ES (pES).…”