Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases
Summary: The total burden of rare diseases is significant worldwide, with over 300 million people being affected. Many rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease...
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| Format: | Article |
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Elsevier
2025-07-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000727 |
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| author | Hau-Yee Ng Wei Ma Wai-Kei J. Lam Chak-Sing Lau Ho-Ming Luk Lisa W.C. Au Shirley S.W. Cheng Josephine S.C. Chong Stephanie Ho Becky M. Ma Shirley Y.Y. Pang Annie T.W. Chu Brian H.Y. Chung |
| author_facet | Hau-Yee Ng Wei Ma Wai-Kei J. Lam Chak-Sing Lau Ho-Ming Luk Lisa W.C. Au Shirley S.W. Cheng Josephine S.C. Chong Stephanie Ho Becky M. Ma Shirley Y.Y. Pang Annie T.W. Chu Brian H.Y. Chung |
| author_sort | Hau-Yee Ng |
| collection | DOAJ |
| description | Summary: The total burden of rare diseases is significant worldwide, with over 300 million people being affected. Many rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease remain genetically undiagnosed and stuck in the diagnostic odyssey after having a cascade of conventional genetic tests. One of the major factors contributing to this is that many types of variants are technically intractable to whole-exome sequencing (WES). In this study, the added diagnostic power of whole-genome sequencing (WGS) for patients with clinically suspected rare diseases was assessed by detecting technically challenging variants. 3,169 patients from the Hong Kong Genome Project (HKGP) were reviewed, identifying 322 individuals having high clinical suspicion of a rare disorder with well-established genetic etiology. Notably, 180 patients have performed at least one previous genetic test. Through PCR-free short-read WGS and a comprehensive in-house analytic pipeline, causative variants were found in 138 patients (138 of 322, 42.9%), 30 of which (30 of 138, 21.7%) are attributed to technically challenging variants. These included 6 variants in low-coverage regions with PCR bias, 2 deep intronic variants, 2 repeat expansions, 19 structural variants, and 2 variants in genes with a homologous pseudogene. The study demonstrated the indispensable diagnostic power of WGS in detecting technically challenging variants and the capability to serve as an all-in-one test for patients with high clinical suspicion of rare diseases. |
| format | Article |
| id | doaj-art-96fa222005be43d3b4c2bb3d05f70529 |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-96fa222005be43d3b4c2bb3d05f705292025-08-20T03:28:11ZengElsevierHGG Advances2666-24772025-07-016310046910.1016/j.xhgg.2025.100469Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseasesHau-Yee Ng0Wei Ma1Wai-Kei J. Lam2Chak-Sing Lau3Ho-Ming Luk4Lisa W.C. Au5Shirley S.W. Cheng6Josephine S.C. Chong7Stephanie Ho8Becky M. Ma9Shirley Y.Y. Pang10Annie T.W. Chu11Brian H.Y. Chung12Hong Kong Genome Institute, Hong Kong, ChinaHong Kong Genome Institute, Hong Kong, ChinaDepartment of Chemical Pathology, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Genetics, Hong Kong Children’s Hospital, Hong Kong, ChinaDepartment of Medicine and Therapeutics, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, ChinaDepartment of Clinical Genetics, Hong Kong Children’s Hospital, Hong Kong, ChinaDepartment of Paediatrics, the Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, ChinaDepartment of Clinical Genetics, Hong Kong Children’s Hospital, Hong Kong, ChinaDivision of Nephrology, Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, ChinaDivision of Neurology, Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, the University of Hong Kong, Hong Kong, ChinaHong Kong Genome Institute, Hong Kong, ChinaHong Kong Genome Institute, Hong Kong, China; Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China; Corresponding authorSummary: The total burden of rare diseases is significant worldwide, with over 300 million people being affected. Many rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease remain genetically undiagnosed and stuck in the diagnostic odyssey after having a cascade of conventional genetic tests. One of the major factors contributing to this is that many types of variants are technically intractable to whole-exome sequencing (WES). In this study, the added diagnostic power of whole-genome sequencing (WGS) for patients with clinically suspected rare diseases was assessed by detecting technically challenging variants. 3,169 patients from the Hong Kong Genome Project (HKGP) were reviewed, identifying 322 individuals having high clinical suspicion of a rare disorder with well-established genetic etiology. Notably, 180 patients have performed at least one previous genetic test. Through PCR-free short-read WGS and a comprehensive in-house analytic pipeline, causative variants were found in 138 patients (138 of 322, 42.9%), 30 of which (30 of 138, 21.7%) are attributed to technically challenging variants. These included 6 variants in low-coverage regions with PCR bias, 2 deep intronic variants, 2 repeat expansions, 19 structural variants, and 2 variants in genes with a homologous pseudogene. The study demonstrated the indispensable diagnostic power of WGS in detecting technically challenging variants and the capability to serve as an all-in-one test for patients with high clinical suspicion of rare diseases.http://www.sciencedirect.com/science/article/pii/S2666247725000727whole genome sequencingrare diseasesstructural variantsnon-coding variantsrepeat expansionspseudogenes |
| spellingShingle | Hau-Yee Ng Wei Ma Wai-Kei J. Lam Chak-Sing Lau Ho-Ming Luk Lisa W.C. Au Shirley S.W. Cheng Josephine S.C. Chong Stephanie Ho Becky M. Ma Shirley Y.Y. Pang Annie T.W. Chu Brian H.Y. Chung Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases HGG Advances whole genome sequencing rare diseases structural variants non-coding variants repeat expansions pseudogenes |
| title | Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| title_full | Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| title_fullStr | Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| title_full_unstemmed | Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| title_short | Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| title_sort | identification of technically challenging variants whole genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases |
| topic | whole genome sequencing rare diseases structural variants non-coding variants repeat expansions pseudogenes |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000727 |
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