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UK's Prenatal Genome and Exome Study Aims to Improve Diagnosis After Abnormal Ultrasound

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NEW YORK (GenomeWeb) – Almost two years after its launch, the UK's Prenatal Assessment of Genomes and Exomes (PAGE) study has recruited about half of its participants and has started to obtain first results to assess whether exome and genome sequencing can improve prenatal diagnoses.

The three-year project is designed to investigate whether prenatal exome or genome sequencing can improve diagnoses for fetuses with structural abnormalities revealed in an ultrasound scan, with the ultimate goal to improve prenatal diagnostics, so parents can make more informed choices about their pregnancy and postnatal care. "By being able to provide a better diagnosis, an explanation what is wrong, the counseling of the parents will hopefully improve and will help to manage the pregnancy and childbirth and help the parents make decisions," said Gabriele Rinck, PAGE's project manager and a researcher at the Wellcome Trust Sanger Institute.

Preceding the project was a pilot study, published in Human Molecular Genetics in 2014, for which scientists at the Sanger Institute sequenced the exomes of 30 fetuses and neonates where prenatal ultrasounds had found structural abnormalities, as well as their parents, and found likely causative variants in three.

Funded by the Health Innovation Challenge Fund, a partnership between the Wellcome Trust and the UK's Department of Health, PAGE officially kicked off in October of 2014 and is run by a consortium of research teams, led by Matt Hurles at the Sanger Institute. Other team members are based at Great Ormond Street Hospital, Birmingham Women's Hospital, the Ethox Centre in Oxford, the University of Birmingham, the University of Cambridge, and the charity Antenatal Results and Choices.

Families are recruited for the project by more than 40 fetal medicine centers across the UK, which also collect the samples. "We are recruiting patients where an abnormality was found in the ultrasound scan," Rinck said.

Such an abnormality occurs in about 3 percent of pregnancies and is usually followed up by genetic testing on material from an amniocentesis or chorionic villus sampling. Those tests, which use techniques such as karyotyping, quantitative fluorescent PCR, or chromosomal microarray analysis, detect a pathogenic variation in fewer than 50 percent of cases, according to the PAGE website, and mainly find insertions, deletions, or duplications up to 10 kilobases in size. The hope is that analyzing these samples by exome or genome sequencing, which has single-base resolution, could increase the diagnostic yield and help researchers discover new genetic disorders.

So far, the PAGE study has consented more than 700 families, Rinck said, but some of these subsequently obtained a diagnosis through routine genetic testing. Of the 700, fewer than 500 have qualified for exome or genome sequencing so far, about half of the 1,000 families the study eventually plans to recruit.

As of last month, PAGE had completely analyzed and clinically reviewed exome data for about 160 families, Rinck said, with the next batch of data scheduled for clinical review in September.

For the study, the Sanger Institute carries out exome sequencing on fetal or placental DNA samples and on DNA from the parents. Another project component, led by Great Ormond Street Hospital, will analyze cell-free DNA from maternal blood, comparing the results with those from the exome sequencing.

For the exome analysis, the Sanger researchers use their established internal sequencing and bioinformatics pipeline, which involves hybridization capture and high-throughput Illumina sequencing. "It's very similar to the procedure that was implemented for the Deciphering Developmental Disorders study," Rinck said. That study, known as DDD, recruited almost 14,000 children with severe undiagnosed development disorders and their parents. Researchers at the Sanger Institute, also led by Hurles, have been sequencing their exomes and performing high-resolution exon-arrayCGH tests.

To analyze the exome data, the Sanger team filters it against a panel of about 1,500 clinical genes that was established for the DDD study. The researchers then present potentially clinically relevant variants to a panel of clinicians, who assess them in conjunction with clinical observations and the fetus' phenotype. As these clinicians are located all over the country, the project uses Congenica's Sapientia platform to share the results, which offers an interface to view the variants and to link to variant databases and literature references.

Only variants deemed to be relevant for the observed ultrasound abnormality are reported to families, and only after they have been validated in an accredited National Health Service diagnostic laboratory and after the pregnancy has ended, Rinck said. Also, the project does not report variants of unknown significance or incidental findings.

The project will also contribute clinical variants to databases such as DECIPHER and will share exome and genome datasets and clinical data with researchers through the European Genome-phenome Archive.

For eight or nine of the 160 families fully analyzed so far, the team has been able to detect clinically relevant variants, Rinck said, translating to a diagnostic rate of about 5 percent. As of last month, four of these results had been validated and returned to the respective clinical teams that recruited the families. "But as we accumulate more knowledge, hopefully, we will be able to push that [number] a bit further," she said. For example, each time the PAGE team analyzes another batch of data, it reprocesses the existing data, which might lead to additional diagnoses.

Also, PAGE plans to select about 20 families for whole-genome sequencing where exome sequencing was unable to find a pathogenic genetic variant. "For that, we will look at phenotypes that have an interesting clinical presentation, and also possibly groups of similar phenotypes that can be analyzed together,"  Rinck said.

Along with the molecular analyses, PAGE also has a social science component that focuses on the experience of parents undergoing the testing, so their views can be taken into account if the test is implemented clinically in the future.

A clinical test, though, is still pretty far away in the future. "There are various ways in which this can be developed and implemented into the clinic, but at the moment, it's still early days, and we need to get more results," Rinck said.

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