Whole-Genome Sequencing Diagnoses Prenatal Chromosomal Rearrangements

Whole genome sequencing of the DNA code of prenatal samples provided a detailed map of the locations of their chromosomal abnormalities in 14 days.

Next generation whole genome sequencing has been used to provide nucleotide level precision after current prenatal diagnostic methods of karyotyping and array comparative genomic hybridization (aCGH).

A team of scientists at Brigham and Women's Hospital (Boston, MA, USA) and Harvard Medical School (Boston, MA, USA) conducted the study which included karyotyping and aCGH studies of the three prenatal samples and provided the first clues of balanced de novo chromosomal rearrangements which prompted the investigation by genomic sequencing.

Clinical consequences of such chromosome rearrangements, which are defined as the relocation of chromosome segments without any loss or gain in genomic material, are rare, not inherited and challenging to predict without knowledge of the precise breakpoints. By using whole genome sequencing, the team determined in a third trimester prenatal sample of the first case that the gene chromodomain-helicase-DNA-binding protein 7 (CHD7), was disrupted. The CHD7 is a causal gene in CHARGE syndrome, and sequencing revealed a single disrupted gene in the second and third pregnancies.

Zehra Ordulu, MD, a medical research fellow and a member of the team, said “Whole genome sequencing was consistent with a diagnosis of CHARGE syndrome, which was not possible based on prenatal imaging and the other commonly used prenatal genetic testing methods. This diagnosis would have changed medical care from an initial plan to repair an isolated heart defect to management of a morbid condition requiring immediate assessment of breathing and feeding difficulties.” The results of this study were presented at the American Society of Human Genetics meeting, held November 6-10, 2012, in San Francisco, (CA, USA).

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Brigham and Women's Hospital
Harvard Medical School