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. 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

David R Murdock  1 , Frank X Donovan  2 , Settara C Chandrasekharappa  2 , Nicole Banks  3 , Carolyn Bondy  3 , Maximilian Muenke  1 , Paul Kruszka  1
Affiliations

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

David R Murdock et al. J Clin Endocrinol Metab. .

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.

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Figures

Figure 1.
Figure 1.
University of California, Santa Cruz, Genome Browser screenshot demonstrating EXCAVATOR2-based CNV prediction on chromosome X for individuals with TS (red = deletion). The first line represents patient 1, known to be mosaic for 45,X/46,XX.
Figure 2.
Figure 2.
LRR plot for patient 1 who had TS with known 45,X/46,XX mosaicism. The mean LRR (red line) was −0.56, corresponding to approximately 64% 45,X and 36% 46,XX. Note full 100% monosomy for distal Xq, confirmed on microarray.
Figure 3.
Figure 3.
University of California, Santa Cruz, Genome Browser screenshots demonstrating EXCAVATOR2-based CNV detection. (a) Y-chromosome material present in patient 14, who had TS. Black bars and blue bars indicate microarray and exome data predictions, respectively. (b) 46,X, iso(Xq) detection using simulated data. Monosomy of Xp and trisomy of Xq is indicated by red bars and blue bars, respectively.
See this image and copyright information in PMC

References

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