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Am J Hematol. 2018 Jan;93(1):8-16. doi: 10.1002/ajh.24917. Epub 2017 Oct 20.

Utility and limitations of exome sequencing in the molecular diagnosis of pediatric inherited platelet disorders.

Author information

1
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
2
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
3
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
4
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia, Pennsylvania.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Division of Genetics, Cooper Health System, Camden, New Jersey.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
8
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Abstract

Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology. We studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to: (1) examine the performance of the exome test for IPD genes, (2) determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, (3) to evaluate the frequency of variants of uncertain significance identified, and (4) to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis. We established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. In conclusion, ES has the potential to molecularly diagnose causes of IPD, and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned.

PMID:
28960434
PMCID:
PMC6366456
DOI:
10.1002/ajh.24917
[Indexed for MEDLINE]
Free PMC Article

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