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Prenatal Exomes Give Diagnosis For Skeletal Abnormalities Seen in Ultrasound

NEW YORK (GenomeWeb) – Prenatal trio exome sequencing and targeted analysis can give molecular diagnoses in most cases of suspected fetal abnormal skeletal growth, a new study has found.

Unexpected fetal abnormalities occur in about 2 percent to 5 percent of pregnancies, and while cytogenic and microarray-based approaches can give diagnoses in about 40 percent of those cases, most remain unsolved.

Researchers led by Lyn Chitty from the Great Ormond Street NHS Foundation Trust in London examined whether targeted prenatal exome sequencing in fetuses and parents could provide diagnoses, do it in a timely manner, and inform pregnancy management. As they reported yesterday in Genetics in Medicine, the researchers found that definitive molecular diagnoses could be made in 81 percent of their cases, which focused on skeletal dysplasias.

"We believe that this will improve prenatal diagnosis and counseling for parents faced with difficult decisions following the detection of unexpected abnormalities in their unborn baby," Chitty and her colleagues wrote in their paper.

A separate project examining prenatal exome sequencing of fetuses with structural abnormalities led by Sanger Institute researchers reported a diagnostic rate of 5 percent, though that number was derived from an early set of samples.

For this study, Chitty and her colleagues recruited pregnant women in the UK who had or were undergoing invasive testing after an ultrasound detected fetal abnormalities that raised the possibility of skeletal dysplasia. Of the 19 cases referred to them, 16 cases went forward for sequencing.

The researchers performed exome sequencing on the Illumina NextSeq500 platform for parental and fetal DNA for all but one of those 16 cases. For case 12, parental and sibling DNA was sequenced, due low levels of fetal DNA. Sanger sequencing of fetal DNA then confirmed any findings, including in case 12. They focused their analysis on a set of 240 genes linked to skeletal dysplasias.

For 13 cases, the researchers were able to make a definitive molecular diagnosis. They uncovered four recessive conditions where the fetus inherited one pathogenic variant from each parent, six de novo dominant pathogenic variants, and two maternally inherited pathogenic variants. One case, they noted, was more complex.

In some of these cases, the researchers found that the condition the fetus had was dominant and inherited from the mother, who did not know she had a genetic condition. For instance, in case 8, the fetus had short, bowed leg bones, and genetic discussions with the mother, who was of short stature, found that she had a history of broken bones, as did some relatives, and discoloration of her teeth. Both she and her unborn child were heterozygous for a pathogenic variant in COL1A2, which confirmed they had autosomal dominant osteogenesis imperfecta type IV.

In the three cases in which the researchers couldn’t provide a diagnosis, two harbored variants of uncertain significance and one had no detectable pathogenic variant.

Chitty and her colleagues noted that they were able to turn around their findings fairly quickly, in 11 to 41 days. The turnaround time, they added, became faster as their approach became more streamlined.

This turnaround time enabled them to provide the information to parents prior to birth and give them more accurate risk counseling. This, researchers noted, aids in decision-making processes for future pregnancies and possible termination of pregnancies. In their study, they noted that some parents did opt for termination in severe cases.

The researchers added, though, that their study was small and needs to be expanded upon to determine whether the results are generalizable.