Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science,Genetics in Medicine

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Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-10-23 , DOI: 10.1038/s41436-020-00984-z
Kelly Schoch ₁ , Cecilia Esteves ₂ , Anna Bican _{3,

4} , Rebecca Spillmann ₁ , Heidi Cope ₁ , Allyn McConkie-Rosell ₁ , Nicole Walley ₁ , Liliana Fernandez ₅ , Jennefer N Kohler ₅ , Devon Bonner ₅ , Chloe Reuter ₅ , Nicholas Stong ₆ , John J Mulvihill _{7,

8} , Donna Novacic ₈ , Lynne Wolfe ₈ , Ayat Abdelbaki ₈ , Camilo Toro ₈ , Cyndi Tifft _{8,

9} , May Malicdan _{8,

10} , William Gahl _{8,

10} , Pengfei Liu _{11,

12} , John Newman ₃ , David B Goldstein ₆ , Jason Hom _{5,

13} , Jacinda Sampson _{5,

14} , Matthew T Wheeler _{5,

13} , , Joy Cogan _{3,

4} , Jonathan A Bernstein _{5,

15} , David R Adams _{8,

9} , Alexa T McCray ₂ , Vandana Shashi ₁

Affiliation

Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Vanderbilt Center for Undiagnosed Disease, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pediatrics, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA.
Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD, USA.
Undiagnosed Diseases Program, Common Fund, NIH Office of the Director, NIH, Bethesda, MD, USA.
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA.
Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Baylor Genetics, Houston, TX, USA.
Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
Department of Neurology, Stanford School of Medicine, Stanford, CA, USA.
Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA.

Purpose

The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.

Methods

We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.

Results

Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease–gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.

Conclusion

Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

中文翻译：

未确诊疾病网络的临床站点：对基因组医学和科学的独特贡献

目的

NIH 未诊断疾病网络 (UDN) 通过应用个性化临床和基因组评估以及创新研究，对患有无法诊断的疾病的参与者进行评估。 UDN 的临床中心对于推进 UDN 使命至关重要；这项研究评估了他们相对于标准临床实践的贡献。

方法

我们分析了 2015 年 7 月至 2019 年 9 月来自四个 UDN 临床中心的回顾性数据，用于诊断、新疾病基因发现和潜在的研究方法。

结果

在 791 名接受评估的个体中，有 231 人接受了 240 项诊断，并发现了 17 个新的疾病基因关联。 UDN 外显子组和基因组测序的直接诊断发生率为 35% (84/240)。尽管基因组测序尚未广泛应用于临床，但我们认为这些在标准临床实践中是容易处理的。大多数（156/240，65%）需要额外的 UDN 驱动的调查，包括先前非诊断性外显子组测序后发生的 90 例诊断和非遗传性的 45 例诊断（19%）。 UDN 驱动的研究包括互补/补充表型分析、基因组变异的创新分析以及功能测定和动物建模的协作科学。