Cited by 231Genomics and Rare DiseasesConnective tissue disorders researchMetabolism and Genetic Disorders

The DOI matches its Crossref record; 111 of the 111 references it cites were found in a registry or an index.

Lessons learned from additional research analyses of unsolved clinical exome cases

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Abstract

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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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.
Venue
Genome Medicine
Published
2017-03-21
Volume
9
Issue
1
Pages
26-26
ISSN
1756-994X (ISSN-L)
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
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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