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Genet Med. 2018 Apr;20(4):464-469. doi: 10.1038/gim.2017.128. Epub 2017 Sep 14.

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

Collaborators (188)

Alejandro ME, Bacino CA, Balasubramanyam A, Bostwick BL, Burrage LC, Chen S, Clark GD, Craigen WJ, Dhar SU, Emrick LT, Graham BH, Hanchard NA, Jain M, Lalani SR, Lee BH, Lewis RA, Azamian MS, Moretti PM, Nicholas SK, Orange JS, Posey JE, Potocki L, Rosenfeld JA, Samson SL, Scott DA, Tran AA, Vogel TP, Zhang J, Bellen HJ, Wangler MF, Yamamoto S, Eng CM, Muzny DM, Ward PA, Yang Y, Goldstein DB, Stong N, Jiang YH, McConkie-Rosell A, Pena LDM, Schoch K, Shashi V, Spillmann RC, Sullivan JA, Walley NM, Beggs AH, Briere LC, Cooper CM, Donnell-Fink LA, Krieg EL, Krier JB, Lincoln SA, Loscalzo J, Maas RL, MacRae CA, Pallais JC, Rodan LH, Silverman EK, Stoler JM, Sweetser DA, Walsh CA, Esteves C, Holm IA, Kohane IS, Mazur P, McCray AT, Might M, Ramoni RB, Splinter K, Bick DP, Birch CL, Boone BE, Brown DM, Dorset DC, Handley LH, Jacob HJ, Jones AL, Lazar J, Levy SE, Newberry JS, Schroeder MC, Strong KA, Worthey EA, Dayal JG, Eckstein DJ, Gould SE, Howerton EM, Krasnewich DM, Mamounas LA, Manolio TA, Mulvihill JJ, Urv TK, Wise AL, Soldatos AG, Brush M, Gourdine JF, Haendel M, Koeller DM, Kyle JE, Metz TO, Waters KM, Webb-Robertson BM, Ashley EA, Bernstein JA, Dries AM, Fisher PG, Kohler JN, Waggott DM, Wheeler MT, Zornio PA, Allard P, Barseghyan H, Dell'Angelica EC, Dillon A, Dipple KM, Dorrani N, Douine ED, Eskin A, Fogel BL, Herzog MR, Lee H, Lipson A, Loo SK, Martínez-Agosto JA, Nelson SF, Palmer CGS, Papp JC, Parker NH, Sinsheimer JS, Vilain E, Zheng A, Adams CJ, Burke EA, Chao KR, Davids M, Draper DD, Estwick T, Frisby TS, Frost K, Gartner V, Godfrey RA, Goheen M, Golas GA, Gordon MG, Groden CA, Hackbarth ME, Hardee I, Johnston JM, Koehler AE, Latham L, Latour YL, Lau CC, Levy DJ, Liebendorfer AP, Macnamara EF, Maduro VV, Markello TC, McCarty AJ, Murphy JL, Nehrebecky ME, Novacic D, Pusey BN, Sadozai S, Schaffer KE, Sharma P, Thomas SP, Tolman NJ, Toro C, Valivullah ZM, Wahl CE, Warburton M, Weech AA, Yu G, Gropman AL, Adams DR, Gahl WA, Malicdan MCV, Tifft CJ, Wolfe LA, Lee PR, Postlethwait JH, Westerfield M, Bican A, Cogan JD, Hamid R, Newman JH, Phillips JA, Robertson AK.

Author information

1
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
2
Institute of Genomic Medicine, Columbia University, New York, New York, USA.
3
Department of Pathology, Duke University Medical Center,Durham, North Carolina, USA.
4
Division of Neurology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
5
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
6
Departments of Dermatology and Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
7
Departments of Pediatrics and Surgery, Duke University Medical Center, Durham, North Carolina, USA.
8
Division of Neuroradiology, Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA.
9
Division of Gastroenterology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
10
Division of Pediatric Nephrology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
11
Department of Orthopedic Surgery, Duke University Medical Center, Durham, North Carolina, USA.
12
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
13
Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
14
Division of Maternal Fetal Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
15
Division of Child Neurology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
16
Division of Medical Genetics, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Abstract

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

PMID:
28914269
PMCID:
PMC5851806
DOI:
10.1038/gim.2017.128
[Indexed for MEDLINE]
Free PMC Article

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