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The researchers found that complete sequencing of exome combined with prenatal genetic testing had identified some fetal abnormalities for which current test methods could not determine the cause of the structural abnormality.
When standard prenatal genetic testing failed to identify the cause of a structural abnormality in the fetus, the addition of sequencing to the complete exome allowed Identify a genetic cause in 10% of the cases examined, said Ronald J. Wapner, MD, of Columbia University, at the Irving Medical Center. in New York and his colleagues.
The number of genetic abnormalities in the fetus appeared to play a role, since a genetic diagnosis was made more frequently in fetuses with several abnormalities compared to those with a single abnormality (19% vs. 6%, respectively), wrote the authors. The lancet.
The authors noted that fetal abnormalities discovered by fetal ultrasound were generally followed by a karyotype test and a chromosomal microarray badysis to identify variants of the number of copies, but more than 60 % of pregnancies do not have a specific genomic diagnosis that can guide future genetic care and counseling.
The team cited research that showed that whole exome sequencing can locate a genetic cause of 25-35% of children with certain types of conbad malformations after negative karyotype test results and chromosome microresion.
"This result in children suggests that [whole-exome sequencing] could constitute an important diagnostic approach in understanding the genetic causes underlying structural abnormalities of the fetus, and this approach could lead to improved perinatal care and genetic prognostic counseling of parents, "the authors wrote.
They explained that, given limited research on the subject, they had conducted a prospective cohort study of pregnant women with structural abnormality during prenatal ultrasound. The team examined data from 234 women with abnormal ultrasound results, but when standard genetic tests were negative, they sequenced the parents 'and fetuses' DNA.
Detection of diagnostic genetic variants causing fetal developmental abnormality based on available whole exome sequencing data was the primary endpoint of the study. study.
Demographically, this sample was different from other genomic studies, the authors note, with almost three-quarters of parents reporting ancestry other than European whites or "sequence data placing the fetus out of the clusters." main indicator components of the European white population ".
Following sequencing of the complete exome, a diagnostic genetic variant was found in 24 out of 234 fetuses, 15 of which were de novo mutations, six of recessive genotypes, and three inherited autosomal dominant from an undiagnosed parent.
In addition, 46 fetuses had suggested mutations but were "not attributable to the structural anomaly", although the authors stated that under the guidelines of the American College of Medical Genetics and Genomics, 15 of the 15 between them would be considered pathogenic.
The diagnosis rate appeared to increase with the increase in the number of fetal abnormalities on ultrasound, the authors noting that in fetuses with ≥3 abnormalities, more than 30% had a diagnostic genetic variant.
An accompanying editorial of Michael E. Talkowski, PhD, and Heidi L. Rehm, PhD, both of Mbadachusetts General Hospital in Boston, said that these data indicate that for now, "a combination" of sequencing Complete exome and "molecular cytogenetic methods" will offer substantial improvements in the accuracy of diagnosis and clinical management of fetal abnormalities.
They argued that these data from this study and a similar one from the same issue of The lancet, "serve as an introduction to [whole-exome sequencing] in prenatal tests and document a convincing rationale for its adoption. The technology is mature, the data is reproducible and the processes are established in many clinical laboratories, "wrote Talkowski and Rehm.
A potential limitation of the data is that researchers have recognized their "limited knowledge" of in utero developmental phenotypes, which may affect their ability to confirm that "an identified variant in utero is causative and represents a genetic diagnosis".
"Future studies are needed to determine whether performing a complete exome sequencing on the fetus during pregnancy will result in improved reproductive care and counseling," Wapner said in a statement.
Wapner said to have no conflict of interest; a co-author revealed a job at AstraZeneca.
Talkowski and Rehm benefit from grants from the National Institutes of Health; Talkowski revealed a collaboration with the authors of the two studies discussed in the editorial; Rehm works for Mbadachusetts General Hospital, Broad Institute of MIT, and Harvard, both of which offer paid genomic tests.
2019-01-31T18: 30: 00-0500
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