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J Genet Couns. 2019 Apr;28(2):213-228. doi: 10.1002/jgc4.1119.

A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing.

Collaborators (196)

Merker J, Schelley S, Enns G, Montgomery S, Zappala Z, Fresard L, Prybol C, Taylor R, McFarland R, Holmes M, Thompson K, Olahova M, Adams DR, Aday A, Alejandro ME, Allard P, Azamian MS, Bacino CA, Baker E, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bellen HJ, Bican A, Bick DP, Birch CL, Boone BE, Bostwick BL, Briere LC, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Chen S, Clark GD, Coakley TR, Cogan JD, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Dries AM, Eckstein DJ, Emrick LT, Enns GM, Eskin A, Esteves C, Estwick T, Fairbrother L, Ferreira C, Fieg EL, Fogel BL, Gahl WA, Glanton E, Godfrey RA, Goldman AM, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, High F, Holm IA, Hom J, Howerton EM, Huang Y, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Koeller DM, Kohane IS, Krasnewich DM, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Merker JD, Metz TO, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Orengo JP, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LD, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Signer R, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Sweetser DA, Tan QK, Tifft CJ, Toro C, Tran AA, Urv TK, Vilain E, Vogel TP, Waggott DM, Wahl CE, Walley NM, Walsh CA, Walker M, Wan J, Wangler MF, Waters KM, Webb-Robertson BM, Westerfield M, Wise AL, Wolfe LA, Yamamoto S, Yang J, Yoon AJ, Yu G, Zhao C, Zheng A.

Author information

1
Center for Undiagnosed Diseases, Stanford University, Stanford, California.
2
Clinical Genomics Program, Stanford Health Care, Stanford, California.
3
Baylor College of Medicine, Houston, Texas.
4
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
5
Department of Neurology, Stanford University School of Medicine, Stanford, California.
6
Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
7
Department of Genetics, Stanford University School of Medicine, Stanford, California.
8
Department of Medicine, Stanford University School of Medicine, Stanford, California.

Erratum in

Abstract

There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.

KEYWORDS:

exome sequencing; genome sequencing; rare diseases; sequencing reanalysis; undiagnosed diseases

PMID:
30964584
DOI:
10.1002/jgc4.1119

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