Abstract
46,XY disorders of sex development (DSD) present with diverse phenotypes and complicated genetic causes. Precise genetic diagnosis contributes to accurate management, and targeted next-generation sequencing (NGS) and whole-exome sequencing are powerful tools for investigating DSD. However, the prevalent variants resulting in 46,XY DSD remain unclear, especially those associated with mild forms, such as isolated hypospadias, inguinal cryptorchidism, and micropenis. From 2019 to 2021, 74 patients with 46,XY DSD (48 typical and 26 mild) from the First Affiliated Hospital of Sun Yat-sen University were enrolled in our cohort study for targeted NGS or whole-exome sequencing. Our targeted 46,XY DSD panel included 108 genes involved in disorders of gonadal development and differentiation, steroid hormone synthesis and activation, persistent Müllerian duct syndrome, idiopathic hypogonadotropic hypogonadism, syndromic disorder, and others. Variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign following the American College of Medical Genetics guidelines. As a result, 28 of 74 (37.8%) patients with pathogenic and/or likely pathogenic variants acquired genetic diagnoses. The Mild DSD patients acquired a diagnosis rate of 30.7%. We detected 44 variants in 28 DSD genes from 31 patients, including 33 novel and 11 reported variants. Heterozygous (65%) and missense (70.5%) variants were the most common. Variants associated with steroid hormone synthesis and activation were the main genetic causes of 46,XY DSD. In conclusion, 46,XY DSD manifests as a series of complicated polygenetic diseases. NGS reveals prevalent variants and improves the genetic diagnoses of 46,XY DSD, regardless of severity.
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Funding
This study was supported by grants from the National Natural Science Foundation of China (81971314). We thank the doctors and nurses in the Department of Pediatric Surgery, First Affiliated Hospital, Sun Yat-Sen University for their help in management of the patients. We also thank the Nuprobe company (Shanghai, China) for its assistance of sequencing and bioinformatic analyses.
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CHD, CS and ZX: designed the study and edited the paper. QGX, PL, KX and ZQL: wrote the paper and carried out the study. All authors participated in the management of the patients. All authors read and approved the final manuscript.
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Xie, QG., Luo, P., Xia, K. et al. 46,XY disorders of sex development: the use of NGS for prevalent variants. Hum Genet 141, 1863–1873 (2022). https://doi.org/10.1007/s00439-022-02465-6
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DOI: https://doi.org/10.1007/s00439-022-02465-6