The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

被引：225

作者：

Gahl, William A. ^{[1
,2
,3
]}

Markello, Thomas C. ^{[2
]}

Toro, Camilo ^{[1
]}

Fajardo, Karin Fuentes ^{[1
]}

Sincan, Murat ^{[3
]}

Gill, Fred ^{[4
]}

Carlson-Donohoe, Hannah ^{[3
]}

Gropman, Andrea ^{[2
,5
]}

Pierson, Tyler Mark ^{[1
,6
]}

Golas, Gretchen ^{[2
]}

Wolfe, Lynne ^{[1
]}

Groden, Catherine ^{[1
,2
]}

Godfrey, Rena ^{[1
]}

Nehrebecky, Michele ^{[1
]}

Wahl, Colleen ^{[1
]}

Landis, Dennis M. D. ^{[1
]}

Yang, Sandra ^{[1
,2
]}

Madeo, Anne ^{[7
]}

Mullikin, James C. ^{[8
]}

Boerkoel, Cornelius F. ^{[1
]}

Tifft, Cynthia J. ^{[1
,2
]}

Adams, David ^{[1
,3
]}

机构：

[1] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA

[2] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA

[3] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA

[4] NIH, Ctr Clin, Bethesda, MD 20892 USA

[5] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA

[6] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA

[7] NIH, Social & Behav Res Branch, Off Rare Dis Res, Off Director, Bethesda, MD 20892 USA

[8] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA

来源：

GENETICS IN MEDICINE | 2012年 / 14卷 / 01期

关键词：

neurological disorders; rare disease; SNP arrays; undiagnosed disease; whole exome sequencing; PARAPLEGIN MUTATIONS; GENE;

D O I：

10.1038/gim.0b013e318232a005

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. Methods: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. Results: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. Conclusion: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.

引用

页码：51 / 59

页数：9

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