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

• Published in: Molecular biology reports Vol. 46; no. 5; pp. 5595 - 5601
• Main Authors: Nagy, Orsolya, Kárteszi, Judit, Hartwig, Marianna, Bertalan, Rita, Jávorszky, Eszter, Erhardt, Éva, Patócs, Attila, Tornóczky, Tamás, Balogh, István, Ujfalusi, Anikó
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2019; Springer Nature B.V
• Subjects: Adrenal glands; Animal Anatomy; Animal Biochemistry; Biomedical and Life Sciences; case studies; Copy number; Cytogenetics; Diagnosis; Differences of sex development; Disorder of Sex Development, 46,XY - diagnosis; Disorder of Sex Development, 46,XY - genetics; Disorders of Sex Development - genetics; DNA Copy Number Variations - genetics; DNA microarrays; Etiology; Exons; Exons - genetics; Female; females; Gene deletion; Genes; Genetic screening; Gonadal dysgenesis; Gonads; heterozygosity; Heterozygote; Histology; Humans; karyotyping; Life Sciences; microarray technology; molecular biology; Morphology; Multiplex Polymerase Chain Reaction - methods; Mutation - genetics; Nucleotide sequence; patients; phenotype; Phenotypes; prognosis; Sequence Deletion - genetics; sexual development; Sexual Development - genetics; Short Communication; Steroidogenic Factor 1 - genetics; Testis - abnormalities; Transcription; transcription factors; Gonadal dysgenesis; 46,XY DSD; Novel partial deletion; MLPA; NR5A1
• ISSN: 0301-4851; 1573-4978; 1573-4978
• DOI: 10.1007/s11033-019-04980-8

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.