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Lessons learned from additional research analyses of unsolved clinical exome cases
Open accessAbstract
BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.
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Moving from targeted gene tests to genomic sequencing allows recursive reanalysis, including reinterpretation as new causal alleles and phenotypes are discovered.
“The transition from targeted gene tests to genomic sequencing enables recursive reanalysis, including reinterpretation of individual sequences on the basis of subsequent discoveries regarding causal disease alleles and their phenotypic consequences137.”
From A brief history of human disease genetics (2020) · cites this paper as [137]
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Self-citation
Metadata
- Authors
- Eldomery, M. K., Coban-Akdemir, Z., Harel, T., Rosenfeld, J. A., Gambin, T., Stray-Pedersen, A., Küry, S., Mercier, S., Lessel, D., Denecke, J., Wiszniewski, W., Penney, S., Liu, P., Bi, W., Lalani, S. R., Schaaf, C. P., Wangler, M. F., Bacino, C. A., Lewis, R. A., Potocki, L., Graham, B. H., Belmont, J. W., Scaglia, F., Orange, J. S., Jhangiani, S. N., Chiang, T., Doddapaneni, H., Hu, J., Muzny, D. M., Xia, F., Beaudet, A. L., Boerwinkle, E., Eng, C. M., Plon, S. E., Sutton, V. R., Gibbs, R. A., Posey, J. E., Yang, Y., & Lupski, J. R.
- Affiliations
- Baylor College of Medicine (US)
- Warsaw University of Technology (PL)
- Centre Hospitalier Universitaire de Nantes (FR)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Lupski, James R.
- ORCID
- Eldomery, Mohammad K.
- Harel, Tamar
- Rosenfeld, Jill A.
- Gambin, Tomasz
- Küry, Sébastien
- Mercier, Sandra
- Lessel, Davor
- Denecke, Jonas
- Wiszniewski, Wojciech
- Liu, Pengfei
- Bi, Weimin
- Lalani, Seema R.
- Schaaf, Christian P.
- Wangler, Michael F.
- Bacino, Carlos A.
- Lewis, Richard Alan
- Potocki, Lorraine
- Graham, Brett H.
- Belmont, John W.
- Scaglia, Fernando
- Orange, Jordan S.
- Jhangiani, Shalini N.
- Hu, Jianhong
- Muzny, Donna M.
- Xia, Fan
- Beaudet, Arthur L.
- Boerwinkle, Eric
- Eng, Christine M.
- Plon, Sharon E.
- Sutton, V. Reid
- Gibbs, Richard A.
- Posey, Jennifer E.
- Yang, Yaping
- Lupski, James R.
- Venue
- Genome Medicine
- Published
- 2017-03-21
- Volume
- 9
- Issue
- 1
- Pages
- 26-26
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC5361813
- OpenAlex
- W2598900401
- Cited by
- 230
- References
- 111
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 22 · 2023: 22 · 2022: 30 · 2021: 27 · 2020: 33 · 2019: 43 · 2018: 30 · 2017: 10
- FWCI
- 21.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Human Genome Research Institute (U54HG006542)
- National Institutes of Health (T32 GM07526, NIH T32 GM07526)
- Genetics Resource Association of Texas
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- monogenic disorders, disease gene discovery, molecular diagnosis, exome sequencing, parent-offspring trios, copy number variation, single nucleotide variants, clinical research collaboration, multiplex families, PURA, TANGO2, GNB5, ATAD3A, MIPEP, DHX30, EBF3
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Adenosine Triphosphatases, DNA-Binding Proteins, Female, Humans, Male, Membrane Proteins, Metalloendopeptidases, Pilot Projects, Transcription Factors, Sequence Analysis, DNA, Computational Biology, Polymorphism, Single Nucleotide, Genomics, Mitochondrial Proteins, Genetic Diseases, Inborn, GTP-Binding Protein beta Subunits, DNA Copy Number Variations, Exome
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