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Cited by 54Genomics and Rare DiseasesConnective tissue disorders researchMetabolism and Genetic Disorders

Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases

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Farwell Hagman, Kelly D., Shinde, Deepali N., Mroske, Cameron, Smith, Erica, Radtke, Kelly, Shahmirzadi, Layla, El-Khechen, Dima, Powis, Zöe +11 more·2017·Genetics in Medicine
DOI 10.1038/gim.2016.95PMC PMC5303763
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Abstract

PURPOSE: Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease. METHODS: Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema. RESULTS: Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of "candidate" and "suspected candidate," respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously. CONCLUSIONS: Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224-235.

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  • Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1, HIKESHI, H3F3B, NKX6-2, and SPATA5, and genes missed in the previous analysis (L1CAM).

    “Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1,12 HIKESHI, 13 H3F3B, 11 NKX6‐2, 14 and SPATA5, 15 and genes missed in the previous analysis (L1CAM).”

    From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [11]

    The Materials and Methods section describes whole-exome sequencing, not the claimed genome-sequencing reanalysis. Searches for AIFM1, HIKESHI, H3F3B, NKX6-2, SPATA5, L1CAM, and the reanalysis wording found no passage in our copy reporting those findings. (LLM, conf=0.76)

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  • Reanalysis identified a de novo missense variant in H3F3B, a hemizygous synonymous variant in AIFM1, and biallelic variants in HIKESHI, NKX6-2, and SPATA5, all previously associated with prominent white matter disease in multiple affected individuals.

    “These included a de novo missense variant in H3F3B (OMIM:601058) (LD_0246), 11 a hemizygous, synonymous variant in AIFM1 (OMIM:300169) (LD_0500),12 and biallelic variants in HIKESHI (OMIM:614908) (LD_0162),13 NKX6‐2 (OMIM:605955) (LD_0527), 14 and SPATA5 (OMIM:613940) (LD_0808),15 all previously associated with prominent white matter disease in multiple affected individuals.”

    From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [11]

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Authors
Farwell Hagman, K. D., Shinde, D. N., Mroske, C., Smith, E., Radtke, K., Shahmirzadi, L., El-Khechen, D., Powis, Z., Chao, E. C., Alcaraz, W. A., Helbig, K. L., Sajan, S. A., Rossi, M., Lu, H.-M., Huether, R., Li, S., Wu, S., Nuñes, M. E., & Tang, S.
Affiliations
  • Ambry Genetics (United States) (US)
  • University of California, Irvine (US)
  • Kaiser Permanente (US)
ORCID
Venue
Genetics in Medicine
Publisher
Elsevier BV
Published
2017-02
Volume
19
Issue
2
Pages
224-235
ISSN
1098-3600 (ISSN-L)
DOI
10.1038/gim.2016.95
PMC
PMC5303763
OpenAlex
W2517462780
Cited by
54
References
6
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 2 · 2019: 10 · 2018: 14 · 2017: 3 · 2014: 1
FWCI
7.27
Type
journal article
Language
en
Update notices
erratum (2018-09-01)
Open access
Licence
Locations
  • Genetics in Medicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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
candidate genes, undiagnosed genetic disorders, genetic diagnosis
MeSH terms
Exome Sequencing, Humans, Mutation, Genetic Diseases, Inborn, Databases, Genetic, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Exome

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