Objective Use next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting.
Design A diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019.
Setting Inpatient and outpatient genetics service at two large academic centres in Singapore.
Patients Inclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay. Exclusion criteria: patients with known genetic disorders, either after clinical assessment or investigations (such as karyotype or chromosomal microarray).
Interventions Use of NGS technology—whole exome sequencing (WES) or whole genome sequencing (WGS).
Main outcome measures (1) Diagnostic yield by sequencing type, (2) diagnostic yield by phenotypical categories, (3) reduction in time to diagnosis and (4) change in clinical outcomes and management.
Results We demonstrate a 37.8% diagnostic yield for WES (n=172) and a 33.3% yield for WGS (n=24). The yield was higher when sequencing was conducted on trios (40.2%), as well as for certain phenotypes (neuromuscular, 54%, and skeletal dysplasia, 50%). In addition to aiding genetic counselling in 100% of the families, a positive result led to a change in treatment in 27% of patients.
Conclusion Genomic sequencing is an effective method for diagnosing rare disease or previous ‘undiagnosed’ disease. The clinical utility of WES/WGS is seen in the shortened time to diagnosis and the discovery of novel variants. Additionally, reaching a diagnosis significantly impacts families and leads to alteration in management of these patients.
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ECT, RF and SSJ are joint corresponding co-authorship.
Collaborators SUREKids Working Group:
KK Women’s and Children’s Hospital, Singapore: Saumya Jamuar, Angeline Lai, Woei Kang Liew,
Wendy Liew, Ee Shien Tan, Mark Koh, Ene Choo Tan, Hai Yang Law, Madeline Ho, Teck Wah Ting, Ene Choo Tan, Ivy Ng, Neha Singh Bhatia, Jiin Ying Lim, Jasmine Goh, Breana Cham, Sylvia Kam, Jyn Ling Kuan, Maggie Brett, Heming Wei, Grace Lin, Kanika Jain, Yuen Ming Tan; National University Hospital Singapore: Denise Goh, Lee Bee Wah, Lynette Shek, Stacey Tay, Ng Kar Hui, Lai Poh San, Swati Tomar, Raman Sethi, Grace Tan, Arthi Shanmugasundaram, Hui-lin Chin; Genome Institute of Singapore: Patrick Tan, Roger Foo, Pauline Ng, Tony Lim, Perumal Dharuman, Devasia Arun George, Deepa Subramanian, Min Xie, Nilesh R Tiwari, Zenia Tiang, Cheuk-Ka Tong, Alexander Lezhava, Sarah B Ng; Institute of Medical Biology: Bruno Reversade, Ray Dunn, Carine Bonnard, Celia Bosso-Lefevre, Nathalie Escande-Beillard; Institute of Molecular and Cell Biology: Byrappa Venkatesh, John Connolly, Alvin Yu-Jin Ng, Sumanty Tohari; Translational Laboratory in Genetic Medicine: Mahmoud Pouladi
Contributors NSB: drafting of the manuscript. NSB, CB, J-LK, MB, HW, HC, CB-L, PD, NE-B, AGD, GL, KJ, Y-JAN, DS, MX,Y-MT, NRT, ZT, ST, CKT, AL, SBN, H-YL, BV, ST, RS, GT, AS, PSL, BR and ECT: sequencing and data analysis, and evaluation of genetic variants. AL, EST, IN, TWT, JYL, BC, CYJG, SK, WK-ML, WKL, DL-MG, RF and SSJ: patient recruitment and phenotypical assessment, and evaluation of genetic variants. BC, JYL, CYJG and SK: genetic counselling, patient recruitment and collection of phenotype data. ECT, RF, BR and SSJ: funding support, supervision, data analysis and drafting of the manuscript. All authors read and approved the final manuscript.
Funding NMRC/CG/M003/2017 and NMRC/CG/006/2013 from the Singapore Ministry of Health’s National Medical Research Council (ECT) 02/FY2016/P1/03-A14 from the SingHealth Duke-NUS Academic Medical Centre (ECT) Clinical Innovation Grant from SingHealth Duke-NUS Paediatric ACP (ECT) IAF 311019 Singapore Ministry of Health’s Biomedical Research Council- (RF and BR) Strategic Positioning Fund on Genetic Orphan Diseases from A*STAR, Singapore (BR) NMRC/CISSP/003/2016 from the Singapore Ministry of Health’s National Medical Research Council (SJ) NMRC 1056/2011 and NMRC 0021/2012 from the Singapore Ministry of Health’s National Medical Research Council (LPS).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data that support the findings of this study are available from the corresponding author upon reasonable request.