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J Clin Endocrinol Metab. 2017 May 1;102(5):1529-1537. doi: 10.1210/jc.2016-3414.

Whole-Exome Sequencing for Diagnosis of Turner Syndrome: Toward Next-Generation Sequencing and Newborn Screening.

Author information

1
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
2
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
3
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.

Abstract

Context:

Turner syndrome (TS) is due to a complete or partial loss of an X chromosome in female patients and is not currently part of newborn screening (NBS). Diagnosis is often delayed, resulting in missed crucial diagnostic and therapeutic opportunities.

Objectives:

This study sought to determine if whole-exome sequencing (WES) as part of a potential NBS program could be used to diagnose TS.

Design, Setting, Patients:

Karyotype, chromosomal microarray, and WES were performed on blood samples from women with TS (n = 27) enrolled in the Personalized Genomic Research study at the National Institutes of Health. Female control subjects (n = 37) and male subjects (n = 27) also underwent WES. Copy number variation was evaluated using EXCAVATOR2 and B allele frequency was calculated from informative single nucleotide polymorphisms. Simulated WES data were generated for detection of low-level mosaicism and complex structural chromosome abnormalities.

Results:

We detected monosomy for chromosome X in all 27 TS samples, including 1 mosaic for 45,X/46,XX and another with previously unreported material on chromosome Y. Sensitivity and specificity were both 100% for the diagnosis of TS with no false-positive or false-negative results. Using simulated WES data, we detected isochromosome Xq and low-level mosaicism as low as 5%.

Conclusion:

We present an accurate method of diagnosing TS using WES, including cases with low-level mosaicism, isochromosome Xq, and cryptic Y-chromosome material. Given the potential use of next-generation sequencing for NBS in many different diseases and syndromes, we propose WES can be used as a screening test for TS in newborns.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01294345.

PMID:
28324009
PMCID:
PMC5443329
DOI:
10.1210/jc.2016-3414
[Indexed for MEDLINE]
Free PMC Article

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