Improvements in next-generation sequencing (NGS) and bioinformatics have revolutionized genomic medicine, significantly improving the diagnosis of rare genetic diseases (RDs). Traditional genetic testing faces challenges due to the complexity of over 8,000 RDs, but exome sequencing (ES) and short-read genome sequencing (srGS) now offer diagnostic rates of 12–63%. The srGS covers 90% of the genome, detecting variants in coding and non-coding regions, while long-read genome sequencing (lrGS) further enhances variant detection.
Global genome projects, including the UK’s 100,000 Genomes Project and the Hong Kong Genome Project (HKGP), are integrating genomic medicine into healthcare.
The HKGP, sequencing up to 50,000 genomes, demonstrates the clinical impact of genome sequencing (GS) in improving RD diagnosis.
Read more about Whole Exome and Whole Genome Sequencing: A guide for geneticists and researchers
Genetic Screening and Diagnostic Yield in HKGP
The HKGP recruited participants with suspected genetic diseases from three major hospitals between July 2021 and December 2022. Recruitment criteria were broad, including monogenic and complex cases, with family members included when possible. Participants underwent srGS using Illumina technology, with variant analysis performed through an in-house bioinformatics pipeline. The lrGS was used for complex variant detection. An automated workflow prioritized variants using phenotype-driven algorithms, with multidisciplinary team reviews ensuring clinical relevance. Diagnosed cases were assessed for clinical impact, including treatment modifications and specialist referrals. Statistical analyses evaluated diagnostic yield across subgroups.
The HKGP enrolled 1,264 individuals (520 probands and 744 relatives) with suspected genetic disorders. The cohort had a near-equal distribution of male and female probands as well as adult and pediatric cases. The most common conditions were neurodevelopmental, neurological, and cancer-related disorders. The GS provided a molecular diagnosis for 28% of probands, primarily detecting SNVs/indels (81%). Diagnostic rates were higher among adults than in children and varied across conditions, with dermatological, ophthalmological, and renal disorders showing the highest yields. GS was more effective in previously untested patients (37% yield) than those with prior genetic testing (23%). Combining short-read and long-read sequencing enhanced variant detection, improving diagnostic accuracy.
Summary
This research is the initial in Asia to document preliminary outcomes from a community-wide GS program for RDs, demonstrating the impact of GS on 1,264 predominantly Chinese participants. A diagnostic rate of 28% was achieved, identifying novel and prevalent variants unique to Southeast Asia, enhancing genomic diversity. Notably, adult probands had a higher diagnostic rate (32%) than pediatric cases (24%). The study highlights the superiority of GS over traditional methods, with srGS and lrGS improving diagnostic accuracy. Findings potentially influenced clinical management in 77% of cases, reducing unnecessary interventions. The HKGP underscores the potential of GS in RD diagnosis, advocating its integration into clinical workflows for healthcare advancements.
Authors: Jacky Wai Kei Lam, Chak Sing Lau, Ho Ming Luk, Lisa Wing Chi Au, Gary C.P. Chan, Will Yap Hang Chan, Shirley Sze Wing Cheng, Timothy Hua Tse Cheng, Li Li Cheung, Yiu Fai Cheung, Josephine Shuk Ching Chong, Annie Tsz Wai Chu, Claudia Ching Yan Chung, Kin Lai Chung, Cheuk Wing Fung, Eva Lai Wah Fung, Yuan Gao, Stephanie Ho, Shirley Pik Ying Hue, Chi-Ho Lee, Tsz Leung Lee, Philip Hei Li, Hei Man Lo, Ivan Fai Man Lo, Herbert Ho Fung Loong, Becky Mingyao Ma, Wei Ma, Shirley Yin Yu Pang, Wai-Kay Seto, Steven Wai Kwan Siu, Ho So, Yuk Him Tam, Wenshu Tang, Rosanna Ming Sum Wong.
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