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BMC Med Genet. 2016 Mar 15;17:23. doi: 10.1186/s12881-016-0286-2.

Targeted next-generation sequencing identification of mutations in patients with disorders of sex development.

Dong Y1, Yi Y2,3,4, Yao H1, Yang Z2, Hu H1, Liu J2, Gao C2, Zhang M2, Zhou L2, Asan2,3,4, Yi X5, Liang Z6.

Author information

1
Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
2
Binhai Genomics Institute, BGI-Tianjin, Tianjin, China.
3
BGI-Shenzhen, Shenzhen, China.
4
Tianjin Enterprise Key Laboratory of Clinical Molecular Diagnostic, Tianjin, China.
5
BGI-Shenzhen, Shenzhen, China. yix@genomics.cn.
6
Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China. zhi.lzliang@gmail.com.

Abstract

BACKGROUND:

The identification of causative mutations is important for treatment decisions and genetic counseling of patients with disorders of sex development (DSD). Here, we designed a new assay based on targeted next-generation sequencing (NGS) to diagnose these genetically heterogeneous disorders.

METHODS:

All coding regions and flanking sequences of 219 genes implicated in DSD were designed to be included on a panel. A total of 45 samples were used for sex chromosome dosage validation by targeted sequencing using the NGS platform. Among these, 21 samples were processed to find the causative mutation.

RESULTS:

The sex chromosome dosages of all 45 samples in this assay were concordant with their corresponding karyotyping results. Among the 21 DSD patients, a total of 11 mutations in SRY, NR0B1, AR, CYP17A1, GK, CHD7, and SRD5A2 were identified, including five single nucleotide variants, three InDels, one in-frame duplication, one SRY-positive 46,XX, and one gross duplication with an estimated size of more than 427,038 bp containing NR0B1 and GK. We also identified six novel mutations: c.230_231insA in SRY, c.7389delA in CHD7, c.273C>G in NR0B1, and c.2158G>A, c.1825A>G, and c.2057_2065dupTGTGTGCTG in AR.

CONCLUSIONS:

Our assay was able to make a genetic diagnosis for eight DSD patients (38.1%), and identified variants of uncertain clinical significance in the other three cases (14.3%). Targeted NGS is therefore a comprehensive and efficient method to diagnose DSD. This work also expands the pathogenic mutation spectrum of DSD.

KEYWORDS:

Disorders of sex development; Novel mutation; Targeted next-generation sequencing

PMID:
26980296
PMCID:
PMC4791760
DOI:
10.1186/s12881-016-0286-2
[Indexed for MEDLINE]
Free PMC Article

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