Abstract
Disorders of sexual development (DSD) are estimated to occur in 1 of 4500 births. Since the genetic etiology of DSD is highly heterogeneous, obtaining a definitive molecular diagnosis by single gene test is challenging. Utilizing a high-throughput sequencing upfront is proposed as an efficient approach to aid in the diagnosis. This study aimed to examine the diagnostic yield of next-generation sequencing in DSD. 32 DSD patients that previously received clinical examinations and single gene tests were selected, with or without a diagnosis. Prior single gene tests were masked, and then samples went through targeted next-generation sequencing of 80 genes from which the diagnostic yield was assessed. A likely diagnosis, with pathogenic or likely pathogenic variants identified, was obtained from nine of the 32 patients (i.e., 28.1%, versus 10% by single gene tests). In another five patients (15.6%), variants of uncertain significance were found. Among 18 variants identified (i.e., 17 single nucleotide variants and one small deletion), eight had not been previously reported. This study supports the notion that next-generation sequencing can be an efficient tool in the clinical diagnosis and variant discovery in DSD.
Highlights
Etiological diagnosis of DSD usually requires a wide spectrum of endocrinological tests, radiological imaging and genetic tests[2]
Whole exome sequencing followed by analysis of selected DSD genes reached a diagnostic yield of 22.5% in 40 patients presenting with 46XY DSD7
Thirty-two Chinese patients with DSD were recruited, each of whom had been subjected to the traditional approach of endocrine analysis and radiological imaging followed by single genetic tests
Summary
Etiological diagnosis of DSD usually requires a wide spectrum of endocrinological tests, radiological imaging and genetic tests[2]. A more recent study by the Liang lab showed a relatively higher yield by a targeted panel sequencing approach, in which a genetic diagnosis in eight out of 21 (38.1%) DSD patients was obtained, with patients harboring copy number variations included[8] These studies demonstrated the diagnostic potential of a high-throughput approach like next-generation sequencing (NGS). Thirty-two Chinese patients with DSD were recruited, each of whom had been subjected to the traditional approach of endocrine analysis and radiological imaging followed by single genetic tests Their prior genetic testing results were blinded in the sample selection, inclusion in this study was not predicated on whether a diagnosis was previously established. This current study aimed to investigate the diagnostic potential of high-throughput sequencing in a mixed cohort of DSD, to provide the mutation spectrum of DSD patients in the Chinese population, and to potentially discover novel genetic variants in DSD
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