Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development

Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. Materials and methods. This study prospectively investigated a total of 267 patients with DSD who presented to Clinical...

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Autores principales:	Diana Miclea, Camelia Alkhzouz, Simona Bucerzan, Paula Grigorescu-Sido, Radu Anghel Popp, Ionela Maria Pascanu, Victoria Cret, Cristina Ghervan, Ligia Blaga, Gabriela Zaharie
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	differences in sex development karyotype SRY CYP21A2 chromosomal microarray next-generation sequencing Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3ba310ab17c9459a953f27c59e2db6be
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spelling	oai:doaj.org-article:3ba310ab17c9459a953f27c59e2db6be2021-11-25T17:21:41ZMolecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development10.3390/diagnostics111121072075-4418https://doaj.org/article/3ba310ab17c9459a953f27c59e2db6be2021-11-01T00:00:00Zhttps://www.mdpi.com/2075-4418/11/11/2107https://doaj.org/toc/2075-4418Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. Materials and methods. This study prospectively investigated a total of 267 patients with DSD who presented to Clinical Emergency Hospital for Children Cluj-Napoca between January 2012 and December 2019. Each patient was clinically, biochemically, and morphologically evaluated. As a first intervention, the genetic test included karyotype + <i>SRY</i> testing. A high value of 17-hydroxyprogesterone was found in 39 patients, in whom strip assay analysis of the <i>CYP21A2</i> gene was subsequently performed. A total of 35 patients were evaluated by chromosomal microarray technique, and 22 patients were evaluated by the NGS of a gene panel. Results. The karyotype analysis established the diagnosis in 15% of the patients, most of whom presented with sex chromosome abnormalities. Genetic testing of <i>CYP21A2</i> established a confirmation of the diagnosis in 44% of patients tested. SNP array analysis was particularly useful in patients with syndromic DSD; 20% of patients tested presented with pathogenic CNVs or uniparental disomy. Gene panel sequencing established the diagnosis in 11 of the 22 tested patients (50%), and the androgen receptor gene was most often involved in these patients. The genes that presented as pathogenic or likely pathogenic variants or variants of uncertain significance were <i>RSPO1</i>, <i>FGFR1</i>, <i>WT1</i>, <i>CHD7</i>, <i>AR</i>, <i>NIPBL</i>, <i>AMHR2</i>, <i>AR</i>, <i>EMX2</i>, <i>CYP17A1</i>, <i>NR0B1</i>, <i>GNRHR</i>, <i>GATA4</i>, and <i>ATM</i> genes. Conclusion. An evaluation following a genetic testing protocol that included karyotype and <i>SRY</i> gene testing, <i>CYP21A2</i> analysis, chromosomal analysis by microarray, and high-throughput sequencing were useful in establishing the diagnosis, with a spectrum of diagnostic yield depending on the technique (between 15 and 50%). Additionally, new genetic variants not previously described in DSD were observed.Diana MicleaCamelia AlkhzouzSimona BucerzanPaula Grigorescu-SidoRadu Anghel PoppIonela Maria PascanuVictoria CretCristina GhervanLigia BlagaGabriela ZaharieMDPI AGarticledifferences in sex developmentkaryotypeSRYCYP21A2chromosomal microarraynext-generation sequencingMedicine (General)R5-920ENDiagnostics, Vol 11, Iss 2107, p 2107 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	differences in sex development karyotype SRY CYP21A2 chromosomal microarray next-generation sequencing Medicine (General) R5-920
spellingShingle	differences in sex development karyotype SRY CYP21A2 chromosomal microarray next-generation sequencing Medicine (General) R5-920 Diana Miclea Camelia Alkhzouz Simona Bucerzan Paula Grigorescu-Sido Radu Anghel Popp Ionela Maria Pascanu Victoria Cret Cristina Ghervan Ligia Blaga Gabriela Zaharie Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
description	Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. Materials and methods. This study prospectively investigated a total of 267 patients with DSD who presented to Clinical Emergency Hospital for Children Cluj-Napoca between January 2012 and December 2019. Each patient was clinically, biochemically, and morphologically evaluated. As a first intervention, the genetic test included karyotype + <i>SRY</i> testing. A high value of 17-hydroxyprogesterone was found in 39 patients, in whom strip assay analysis of the <i>CYP21A2</i> gene was subsequently performed. A total of 35 patients were evaluated by chromosomal microarray technique, and 22 patients were evaluated by the NGS of a gene panel. Results. The karyotype analysis established the diagnosis in 15% of the patients, most of whom presented with sex chromosome abnormalities. Genetic testing of <i>CYP21A2</i> established a confirmation of the diagnosis in 44% of patients tested. SNP array analysis was particularly useful in patients with syndromic DSD; 20% of patients tested presented with pathogenic CNVs or uniparental disomy. Gene panel sequencing established the diagnosis in 11 of the 22 tested patients (50%), and the androgen receptor gene was most often involved in these patients. The genes that presented as pathogenic or likely pathogenic variants or variants of uncertain significance were <i>RSPO1</i>, <i>FGFR1</i>, <i>WT1</i>, <i>CHD7</i>, <i>AR</i>, <i>NIPBL</i>, <i>AMHR2</i>, <i>AR</i>, <i>EMX2</i>, <i>CYP17A1</i>, <i>NR0B1</i>, <i>GNRHR</i>, <i>GATA4</i>, and <i>ATM</i> genes. Conclusion. An evaluation following a genetic testing protocol that included karyotype and <i>SRY</i> gene testing, <i>CYP21A2</i> analysis, chromosomal analysis by microarray, and high-throughput sequencing were useful in establishing the diagnosis, with a spectrum of diagnostic yield depending on the technique (between 15 and 50%). Additionally, new genetic variants not previously described in DSD were observed.
format	article
author	Diana Miclea Camelia Alkhzouz Simona Bucerzan Paula Grigorescu-Sido Radu Anghel Popp Ionela Maria Pascanu Victoria Cret Cristina Ghervan Ligia Blaga Gabriela Zaharie
author_facet	Diana Miclea Camelia Alkhzouz Simona Bucerzan Paula Grigorescu-Sido Radu Anghel Popp Ionela Maria Pascanu Victoria Cret Cristina Ghervan Ligia Blaga Gabriela Zaharie
author_sort	Diana Miclea
title	Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
title_short	Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
title_full	Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
title_fullStr	Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
title_full_unstemmed	Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development
title_sort	molecular and cytogenetic analysis of romanian patients with differences in sex development
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3ba310ab17c9459a953f27c59e2db6be
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Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development

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