title: Clinical diagnosis by whole-genome sequencing of a prenatal sample.
abstract: Conventional cytogenetic testing offers low-resolution detection of balanced karyotypic abnormalities but cannot provide the precise, gene-level knowledge required to predict outcomes. The use of high-resolution whole-genome deep sequencing is currently impractical for the purpose of routine clinical care. We show here that whole-genome "jumping libraries" can offer an immediately applicable, nucleotide-level complement to conventional genetic diagnostics within a time frame that allows for clinical action. We performed large-insert sequencing of DNA extracted from amniotic-fluid cells with a balanced de novo translocation. The amniotic-fluid sample was from a patient in the third trimester of pregnancy who underwent amniocentesis because of severe polyhydramnios after multiple fetal anomalies had been detected on ultrasonography. Using a 13-day sequence and analysis pipeline, we discovered direct disruption of CHD7, a causal locus in the CHARGE syndrome (coloboma of the eye, heart anomaly, atresia of the choanae, retardation, and genital and ear anomalies). Clinical findings at birth were consistent with the CHARGE syndrome, a diagnosis that could not have been reliably inferred from the cytogenetic breakpoint. This case study illustrates the potential power of customized whole-genome jumping libraries when used to augment prenatal karyotyping.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.forename: Zehra
authors.initials: Z
authors.lastname: Ordulu
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.forename: Carol B
authors.initials: CB
authors.lastname: Benson
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.forename: Susan
authors.initials: S
authors.lastname: Connolly
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.forename: Naveed
authors.initials: N
authors.lastname: Hussain
authors.forename: Shahrin
authors.initials: S
authors.lastname: Pereira
authors.forename: Jonathan
authors.initials: J
authors.lastname: Picker
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Louise E
authors.initials: LE
authors.lastname: Wilkins-Haug
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
mesh_terms: D000328:Adult; D058747:CHARGE Syndrome / Q000175:diagnosis / Q000235:genetics*; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000175:diagnosis*; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human; D015698:Genomic Library; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D059785:Karyotype; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D014178:Translocation, Genetic; D016216:Ultrasonography, Prenatal