Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

Brendan Lee, MD, PhD, Baylor College of Medicine Next generation sequencing and multi-omic approaches for diagnosing skeletal diseases The rapid advances in next generation sequencing technologies have empowered a rapid increase in genotype-phenotype correlations in rare skeletal diseases. There are currently close to 4000 known disease genes but over 6000 unique genotypephenotype associations underscoring increasing discovery of novel phenotypic manifestations caused by mutations in the same gene (Online Mendelian Inheritance in Man, OMIM). Two thousand six hundred (2600) of these clinical phenotypes involve skeletal manifestations. Hence, there is an enormous opportunity for discoveries in skeletal development and homeostasis. Beyond the importance of the diagnostic impact on patients, these correlations point to altered protein function beyond traditional loss of function and highlight the contribution tissue-dependent, structure-function correlations to diverse skeletal phenotypes. Past approaches to diagnoses was based on targeted gene Sanger sequencing. Currently, multi-gene panels using next generation sequencing allow for high coverage analysis enabling detection of single nucleotide variation, insertiondeletions, and copy number variations. Capture-based whole exome sequencing has the potential of high throughput analysis of known and potential new gene associations as well as identification of blended phenotypes due to oligogenic inheritance. As part of the NIH Undiagnosed Diseases Network (UDN), the Baylor College of Medicine UDN Clinical site has implemented a multi-omic approach to diagnosis including whole genome sequencing and RNAsequencing of blood and fibroblasts. Whole genome sequencing has further identified regulatory mutations that have the potential to alter allele specific expression, splicing, and isoform utilization. Combined RNAsequence analysis of blood and fibroblast RNA could identify 80% of known OMIM skeletal dysplasia genes and correlated with potential pathogenicity of variants identified by NGS. Hence, a multi-omic approach combining whole exome/genome sequencing and RNAsequencing can increase the yield of diagnostic findings in rare skeletal diseases as well as point to novel genotype-phenotype correlations that will inform new structure function discoveries. Struan Grant, PhD, Children’s Hospital of Philadelphia Higher order chromatin structure and distal genetic interactions in the diagnosis of skeletal diseases