Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure

Steven M. Harrison, Ian M. Campbell, Melise Keays, Candace F. Granberg, Carlos Villanueva, Grace Tannin, Andrew R. Zinn, Diego H. Castrillon, Chad A. Shaw, Pawel Stankiewicz, Linda A. Baker

Research output: Contribution to journalArticle

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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 0.23Mb 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.

Original languageEnglish (US)
Pages (from-to)2487-2494
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume161
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

XY Disorders of Sex Development 46
Primary Ovarian Insufficiency
Disorders of Sex Development
Hypospadias
Multiplex Polymerase Chain Reaction
Pedigree
Mutation
Steroidogenic Factor 1
Gonadal Dysgenesis
Cytoplasmic and Nuclear Receptors
Genes
Chromosomes
Mothers
Phenotype

Keywords

  • 46,XY disorders of sex development
  • 46,XY gonadal dysgenesis
  • Hypospadias
  • NR5A1
  • Premature ovarian failure
  • SF-1 transcription factor

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. / 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.

In: American Journal of Medical Genetics, Part A, Vol. 161, No. 10, 10.2013, p. 2487-2494.

Research output: Contribution to journalArticle

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. / Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. In: American Journal of Medical Genetics, Part A. 2013 ; Vol. 161, No. 10. pp. 2487-2494.
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AU - Granberg, Candace F.

AU - Villanueva, Carlos

AU - Tannin, Grace

AU - Zinn, Andrew R.

AU - Castrillon, Diego H.

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