title: Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure.
abstract: The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 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 NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 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 NR5A1 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 NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 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 NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harrison
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.forename: Melise
authors.initials: M
authors.lastname: Keays
authors.forename: Candace F
authors.initials: CF
authors.lastname: Granberg
authors.forename: Carlos
authors.initials: C
authors.lastname: Villanueva
authors.forename: Grace
authors.initials: G
authors.lastname: Tannin
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Zinn
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Linda A
authors.initials: LA
authors.lastname: Baker
mesh_terms: D000328:Adult; D001483:Base Sequence; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D056915:DNA Copy Number Variations; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis* / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: D054339:Steroidogenic Factor 1
keywords: 46,XY disorders of sex development; 46,XY gonadal dysgenesis; NR5A1; SF-1 transcription factor; hypospadias; premature ovarian failure
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