Singapore Undiagnosed Disease Program: Genomic Analysis aids Diagnosis and Clinical Management
Neha Bhatia, Jiin Ying Lim, Carine Bonnard, Jyn-Ling Kuan, Maggie Brett, Heming Wei, Breana Cham, Hui‐Lin Chin, Célia Bosso-Lefèvre, Perumal Dharuman, Nathalie Escande‐Beillard, Arun George Devasia, Chew Yin Jasmine Goh, Sylvia Kam, Wendy K.M. Liew, Woei Kang Liew, Grace Lin, Kanika Jain, Alvin Yu Jin Ng, Deepa Subramanian, Min Xie, Yuen-Ming Tan, Nilesh R. Tawari, Zenia Tiang, Teck Wah Ting, Sumanty Tohari, Cheuk Ka Tong, Alexander Lezhava, Sarah Ng, Hai Yang Law, Byrappa Venkatesh, Swati Tomar, Raman Sethi, Grace Ping Ping Tan, Arthi Shanmugasundaram, Denise Goh, Poh San Lai, Angeline Lai, Ee Shien Tan, Ivy Ng, Bruno Reversades, Ene‐Choo Tan, Roger Foo, Saumya Shekhar Jamuar
Abstract
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.