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THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development

Disclosure: J. Kim: None. S. Park: None. S. Hwang: None. J. Yoon: None. G. Kim: None. H. Yoo: None. J. Choi: None. Background: Disorders of sexual development (DSDs) is a group of congenital conditions associated with discordant development of chromosomal, gonadal, and anatomical sex. Sex developmen...

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Autores principales: Kim, Ja Hye, Park, Soyoung, Hwang, Soojin, Yoon, Ji-Hee, Kim, Gu-Hwan, Yoo, Han-Wook, Choi, Jin-Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10554178/
http://dx.doi.org/10.1210/jendso/bvad114.1436
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author Kim, Ja Hye
Park, Soyoung
Hwang, Soojin
Yoon, Ji-Hee
Kim, Gu-Hwan
Yoo, Han-Wook
Choi, Jin-Ho
author_facet Kim, Ja Hye
Park, Soyoung
Hwang, Soojin
Yoon, Ji-Hee
Kim, Gu-Hwan
Yoo, Han-Wook
Choi, Jin-Ho
author_sort Kim, Ja Hye
collection PubMed
description Disclosure: J. Kim: None. S. Park: None. S. Hwang: None. J. Yoon: None. G. Kim: None. H. Yoo: None. J. Choi: None. Background: Disorders of sexual development (DSDs) is a group of congenital conditions associated with discordant development of chromosomal, gonadal, and anatomical sex. Sex development is a complex process with a precise synergistic temporal-spatial transcriptional regulation of multiple genes. Advances in next-generation sequencing (NGS) techniques have achieved genetic diagnosis for up to 40 % of 46,XY DSDs. This study investigated the etiological distribution of DSDs identified by NGS. Methods: This study included 70 patients with DSDs (56 patients with 46,XY DSD and 14 patients with 46,XX DSD). Molecular genetic analysis was performed using targeted gene panel sequencing (n = 43) and whole-exome sequencing (WES, n = 26), including 25 patients for the first-line test and one without sequence variants by targeted gene panel sequencing. Whole-genome sequencing (WGS) was performed on 7 patients, including two patients for the first-line test and five patients without sequence variants by targeted gene panel sequencing or WES. Results: Patients with DSDs presented in infancy with ambiguous genitalia and at older children with aberrant pubertal development or discordance between karyotype and external genitalia. Twenty-four of 56 patients (42.9%) with 46,XY DSD were reared female, and 5 of 14 patients (35.7%) with 46,XX DSD were raised as a male. Pathogenic or likely pathogenic variants were identified in 21 of 56 patients with 46,XY DSD (37.5%); however, no rare sequence variants were found in patients with 46,XX DSD. The AR variants were the most common (8/70, 11.4%), followed by CYP17A1 (4/70, 5.7%), SRD5A2 (4/70, 5.7%), NR5A1 (2/70, 2.8%), GATA4 (1/70, 1.4%), MYRF (1/70, 1.4%), and deletion of DMRT1/2 (1/70, 1.4%). Mutation-positive patients with 46, XY DSD were assigned as female more frequently than mutation-negative patients (19/21 vs. 6/35, P-value <0.001). The lower diagnostic yield was observed in patients with a less severe phenotype, such as hypospadias or micropenis. Conclusions: This study demonstrated that genetic etiologies could be identified in 37.5% of patients with 46,XY DSD, whereas there were no genetic variants in patients with 46,XX DSD. Patients with a more severe phenotype were more likely to have a conclusive genetic diagnosis. NGS is a helpful technique to improve diagnostic efficiency in patients with DSD because of phenotypic and genetic heterogeneity. Presentation: Thursday, June 15, 2023
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spelling pubmed-105541782023-10-06 THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development Kim, Ja Hye Park, Soyoung Hwang, Soojin Yoon, Ji-Hee Kim, Gu-Hwan Yoo, Han-Wook Choi, Jin-Ho J Endocr Soc Pediatric Endocrinology Disclosure: J. Kim: None. S. Park: None. S. Hwang: None. J. Yoon: None. G. Kim: None. H. Yoo: None. J. Choi: None. Background: Disorders of sexual development (DSDs) is a group of congenital conditions associated with discordant development of chromosomal, gonadal, and anatomical sex. Sex development is a complex process with a precise synergistic temporal-spatial transcriptional regulation of multiple genes. Advances in next-generation sequencing (NGS) techniques have achieved genetic diagnosis for up to 40 % of 46,XY DSDs. This study investigated the etiological distribution of DSDs identified by NGS. Methods: This study included 70 patients with DSDs (56 patients with 46,XY DSD and 14 patients with 46,XX DSD). Molecular genetic analysis was performed using targeted gene panel sequencing (n = 43) and whole-exome sequencing (WES, n = 26), including 25 patients for the first-line test and one without sequence variants by targeted gene panel sequencing. Whole-genome sequencing (WGS) was performed on 7 patients, including two patients for the first-line test and five patients without sequence variants by targeted gene panel sequencing or WES. Results: Patients with DSDs presented in infancy with ambiguous genitalia and at older children with aberrant pubertal development or discordance between karyotype and external genitalia. Twenty-four of 56 patients (42.9%) with 46,XY DSD were reared female, and 5 of 14 patients (35.7%) with 46,XX DSD were raised as a male. Pathogenic or likely pathogenic variants were identified in 21 of 56 patients with 46,XY DSD (37.5%); however, no rare sequence variants were found in patients with 46,XX DSD. The AR variants were the most common (8/70, 11.4%), followed by CYP17A1 (4/70, 5.7%), SRD5A2 (4/70, 5.7%), NR5A1 (2/70, 2.8%), GATA4 (1/70, 1.4%), MYRF (1/70, 1.4%), and deletion of DMRT1/2 (1/70, 1.4%). Mutation-positive patients with 46, XY DSD were assigned as female more frequently than mutation-negative patients (19/21 vs. 6/35, P-value <0.001). The lower diagnostic yield was observed in patients with a less severe phenotype, such as hypospadias or micropenis. Conclusions: This study demonstrated that genetic etiologies could be identified in 37.5% of patients with 46,XY DSD, whereas there were no genetic variants in patients with 46,XX DSD. Patients with a more severe phenotype were more likely to have a conclusive genetic diagnosis. NGS is a helpful technique to improve diagnostic efficiency in patients with DSD because of phenotypic and genetic heterogeneity. Presentation: Thursday, June 15, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10554178/ http://dx.doi.org/10.1210/jendso/bvad114.1436 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Pediatric Endocrinology
Kim, Ja Hye
Park, Soyoung
Hwang, Soojin
Yoon, Ji-Hee
Kim, Gu-Hwan
Yoo, Han-Wook
Choi, Jin-Ho
THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title_full THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title_fullStr THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title_full_unstemmed THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title_short THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development
title_sort thu185 molecular etiologic spectrum of patients with 46,xy and 46,xx disorders of sex development
topic Pediatric Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10554178/
http://dx.doi.org/10.1210/jendso/bvad114.1436
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