Screening and familial characterization of copy‐number variations in NR5A1 in 46, XY disorders of sex development and premature ovarian failure. Issue 10 (5th August 2013)

• Record Type: Journal Article
• Authors: Harrison, Steven M.; Campbell, Ian M.; Keays, Melise; Granberg, Candace F.; Villanueva, Carlos; Tannin, Grace; Zinn, Andrew R.; Castrillon, Diego H.; Shaw, Chad A.; Stankiewicz, Pawel; Baker, Linda A.
• Is Part Of: American journal of medical genetics. Volume 161:Issue 10(2013:Oct.)
• Page Start: 2487
• Page End: 2494
• Publication Date: 2013-08-05
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.36084
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="ajmga36084-sec-0001" sec-type="section"> <p>The <italic>NR5A1</italic> gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by <italic>NR5A1</italic> sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46, XY patients and premature ovarian failure (POF) in 46, XX patients. Previous reports have identified four families with a history of both 46, XY DSD and 46, XX POF carrying segregating <italic>NR5A1</italic> sequence mutations. Recently, three 46, XY DSD sporadic cases with <italic>NR5A1</italic> microdeletions have been reported. Here, we identify the first <italic>NR5A1</italic> microdeletion transmitted in a pedigree with both 46, XY DSD and 46, XX POF. A 46, XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the <italic>NR5A1</italic> gene. Based on this finding, we screened patients with unexplained 46, XY DSD (n = 11), proximal hypospadias (n = 21) and 46, XX POF (n = 36) for possible <italic>NR5A1</italic> copy‐number variations (CNVs) via multiplex ligation‐dependent probe amplification (MLPA), but did not identify any additional CNVs involving <italic>NR5A1</italic>. These data suggest that <italic>NR5A1</italic> CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial <italic>NR5A1</italic> CNV transmitting in a pedigree, causing both the male and female phenotypes associated with <italic>NR5A1</italic> mutations, and the first report of a <italic>NR5A1</italic> CNV associated with POF. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>