Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.715042
Keywords
targeted exome sequencing; genetic skeletal dysplasia; molecular diagnosis; genetics evaluation; clinical utility
Categories
Funding
- National Key Research and Development Program of China [2018YFA0800801]
- National Basic Research Program of China [2014CB942903]
- National Natural Science Foundation of China (NSFC) [81770872, 81900807, 81770874, 81770871]
- Clinical Science and Technology Innovation Project of Shanghai Shenkang
- Hospital Development Center [SHDC12018120]
- Shanghai Key Clinical Center for Metabolic Disease, Shanghai Health Commission Grant [2017ZZ01013]
- Shanghai Municipal Key Clinical Specialty
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In this study, targeted exome sequencing (TES) was used to diagnose 223 probands with genetic skeletal dysplasias (GSDs), resulting in molecular diagnoses for 110 individuals and confirmation of 129 pathogenic/likely pathogenic variants. The high diagnostic rate of TES in GSDs could aid clinicians in confirming molecular diagnoses, guiding treatment, and providing genetic counseling.
Genetic skeletal dysplasias (GSDs) are a type of disease with complex phenotype and high heterogeneity, characterized by cartilage and bone growth abnormalities. The variable phenotypes of GSD make clinical diagnosis difficult. To explore the clinical utility of targeted exome sequencing (TES) in the diagnosis of GSD, 223 probands with suspected GSD were enrolled for TES with a panel of 322 known disease-causing genes. After bioinformatics analysis, all candidate variants were prioritized by pathogenicity. Sanger sequencing was used to verify candidate variants in the probands and parents and to trace the source of variants in family members. We identified the molecular diagnoses for 110/223 probands from 24 skeletal disorder groups and confirmed 129 pathogenic/likely pathogenic variants in 48 genes. The overall diagnostic rate was 49%. The molecular diagnostic results modified the diagnosis in 25% of the probands, among which mucopolysaccharidosis and spondylo-epi-metaphyseal dysplasias were more likely to be misdiagnosed. The clinical management of 33% of the probands also improved; 21 families received genetic counseling; 4 families accepted prenatal genetic diagnosis, 1 of which was detected to carry pathogenic variants. The results showed that TES achieved a high diagnostic rate for GSD, helping clinicians confirm patients' molecular diagnoses, formulate treatment directions, and carry out genetic counseling. TES could be an economical diagnostic method for patients with GSD.
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