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Session


Keywords: Mendelian disorder; Dysmorphology; Methodology; Genome sequencing

Authors:
J.T. Shieh 1,2; M. Penon-Portmann 2; M. Levy-Sakin 3; A. Slavotinek 1,2; H. Perry 6; D. Beleford 2; A. Sharo 4; R. Gallagher 1,2; S.E. Brenner 4; Z. Qi 5; J. Yu 5; J. Tenney 2; O. Klein 1,2,6; D. Martin 8; P. Kwok 1,3,7; D. Boffelli 8

Affiliations:
1) Institute for Human Genetics, University of California San Francisco, San Francisco, CA; 2) Division of Medical Genetics, Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA; 3) Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA; 4) Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA; 5) Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA; 6) Craniofacial Center, Craniofacial Biology and Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA; 7) Department of Dermatology, University of California San Francisco, San Francisco, CA; 8) Children's Hospital Oakland Research Institute, Benioff Children's Hospital Oakland, Oakland, CA


Genome analyses that generate very long haplotypes may facilitate diagnostic testing, particularly through the detection of structural variants. In this study, we probed the ability of de novo genome assemblies to improve identification of genetic lesions responsible for undiagnosed conditions. We hypothesized that a single genetic test could detect all types of genetic variants, including coding, noncoding, and structural variants. We used a hybrid linked read/optical mapping approach on undiagnosed cases, using a trio design. Potential diagnostic candidate variants were verified using secondary testing and reviewed by a multidisciplinary team. Clinically significant structural rearrangement and copy number variants were detected, and we were able to determine novel phasing data that discerns allele-specific mutations. We conclude that de novo genome assemblies can provide detailed diagnostic information beyond that provided by typical clinical sequencing technologies.