Balanced Chromosome Rearrangements Rapidly Annotate the Morbid Human Genome. T. Kammin1, K. E. Wong1, B. B. Currall1,2, Z. Ordulu1,2, H. Brand2,3, V. Pillalamarri3, C. Hanscom3, I. Blumenthal3, J. F. Gusella2,3,4,5,6, E. C. Liao7,8,9, M. E. Talkowski2,3,4,6, C. C. Morton1,2,6,10 1) Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Womens Hospital, Boston, MA; 2) Harvard Medical School, Boston, MA; 3) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 4) Department of Neurology, Massachusetts General Hospital, Boston, MA; 5) Department of Genetics, Harvard Medical School, Boston, MA; 6) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA; 7) Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 8) Division of Plastic and Reconstructive Surgery, MA General Hospital, Harvard Medical School, Boston, MA; 9) Harvard Stem Cell Institute, Boston, MA; 10) Department of Pathology, Brigham and Womens Hospital, Boston, MA.

   The Developmental Genome Anatomy Project (DGAP) is a collaborative effort to identify novel genes critical for human development and disease pathogenesis through study of genetic loci disrupted or dysregulated by balanced chromosomal rearrangements. We perform Whole Genome Sequencing (WGS) of rearrangement breakpoints of every subject and use cellular, mouse and zebrafish models to validate the role of candidate genes. To date, we have enrolled over 295 families and sequenced 131 cases, identifying over 175 genes at 76% of breakpoints. We summarize some of our recent findings and scientific surprises, focusing on three DGAP cases to highlight the importance of analyzing apparently balanced chromosomal rearrangements to discover the etiology of rare diseases. DGAP162 presents with severe developmental delay; sequencing showed disruption of LINC00299 resulting in its upregulated expression and revealing that a noncoding RNA can be associated with a severe developmental phenotype. DGAP056 disrupted C2orf43, associated with craniofacial abnormalities, sensorineural hearing loss and early onset prostate cancer (age 38 years). Our mouse KO model supports the role of this gene in hearing loss and prostate cancer. Identification of C2orf43 as a cholesterol esterase illuminates a previously unrecognized metabolic pathway common to deafness and cancer. Implementation of our large insert jumping library WGS approach to explore de novo balanced rearrangements detected prenatally permits reporting of nucleotide level precision results within two weeks, of particular value in these time-sensitive situations. Five cases analyzed to date have revealed that, compared to conventional karyotyping methods, WGS approaches are an accurate and timely method of refining chromosome rearrangements. We discuss DGAP247 and report the impact of a prenatal next-generation sequencing result from the Mothers perspective. DGAP allows us to annotate poorly defined areas of the genome and discover previously unknown developmental networks. The impact of DGAP is also therapeutic for families, providing a definitive diagnosis in an often unique clinical disorder.

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