The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development

Orsolya Nagy, Judit Kárteszi, Marianna Hartwig, Rita Bertalan, Eszter Jávorszky, E. Erhardt, A. Patócs, T. Tornóczky, I. Balogh, Anikó Ujfalusi

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Abstract

Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.

Original languageEnglish
JournalMolecular Biology Reports
DOIs
Publication statusPublished - Jan 1 2019

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Sexual Development
Gonadal Dysgenesis
Multiplex Polymerase Chain Reaction
Gene Deletion
Exons
Genes
46,XY Gonadal Dysgenesis
Cytogenetic Analysis
Gonads
Regulator Genes
Microarray Analysis
Adrenal Glands
Karyotype
Maintenance
Phenotype
Mutation

Keywords

  • 46,XY DSD
  • Gonadal dysgenesis
  • MLPA
  • Novel partial deletion
  • NR5A1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

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title = "The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development",
abstract = "Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50{\%} of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.",
keywords = "46,XY DSD, Gonadal dysgenesis, MLPA, Novel partial deletion, NR5A1",
author = "Orsolya Nagy and Judit K{\'a}rteszi and Marianna Hartwig and Rita Bertalan and Eszter J{\'a}vorszky and E. Erhardt and A. Pat{\'o}cs and T. Torn{\'o}czky and I. Balogh and Anik{\'o} Ujfalusi",
year = "2019",
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doi = "10.1007/s11033-019-04980-8",
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T1 - The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development

AU - Nagy, Orsolya

AU - Kárteszi, Judit

AU - Hartwig, Marianna

AU - Bertalan, Rita

AU - Jávorszky, Eszter

AU - Erhardt, E.

AU - Patócs, A.

AU - Tornóczky, T.

AU - Balogh, I.

AU - Ujfalusi, Anikó

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.

AB - Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.

KW - 46,XY DSD

KW - Gonadal dysgenesis

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KW - Novel partial deletion

KW - NR5A1

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