Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1

Eggers, Stefanie, Smith, Katherine R., Bahlo, Melanie, Looijenga, Leendert H. J., Drop, Stenvert L. S., Juniarto, Zulfa A., Harley, Vincent R., Koopman, Peter, Faradz, Sultana M. H. and Sinclair, Andrew H. (2014) Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1. European Journal of Human Genetics, 23 4: 486-493. doi:10.1038/ejhg.2014.130

Author Eggers, Stefanie
Smith, Katherine R.
Bahlo, Melanie
Looijenga, Leendert H. J.
Drop, Stenvert L. S.
Juniarto, Zulfa A.
Harley, Vincent R.
Koopman, Peter
Faradz, Sultana M. H.
Sinclair, Andrew H.
Title Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1
Journal name European Journal of Human Genetics   Check publisher's open access policy
ISSN 1018-4813
Publication date 2014-08-06
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ejhg.2014.130
Open Access Status Not yet assessed
Volume 23
Issue 4
Start page 486
End page 493
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
Abstract Disorders of sex development (DSDs) encompass a broad spectrum of conditions affecting the development of the gonads and genitalia. The underlying causes for DSDs include gain or loss of function variants in genes responsible for gonad development or steroidogenesis. Most patients with DSD have an unknown genetic etiology and cannot be given an accurate diagnosis. We used whole exome capture and massively parallel sequencing to analyse a large family with 46,XY DSD and 46,XX premature ovarian insufficiency. In addition, we used a recently developed method for linkage analysis using genotypes extracted from the MPS data. This approach identified a unique linkage peak on chromosome 9 and a novel, 3 bp, in-frame deletion in exon six of NR5A1 (steroidogenic factor-1 or SF1) in all affected individuals. We confirmed that the variant disrupts the SF1 protein and its ability to bind and regulate downstream genes. NR5A1 has key roles at multiple points in gonad development and steroidogenic pathways. The variant described here affects the function of SF1 in early testis development and later ovarian function, ultimately leading to the 46,XY DSD and 46,XX premature ovarian insufficiency phenotypes, respectively. This study shows that even at low coverage, whole exome sequencing, when combined with linkage analysis, can be a powerful tool to identify rapidly the disease-causing variant in large pedigrees.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 546517
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 14 times in Scopus Article | Citations
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Created: Thu, 16 Oct 2014, 00:14:34 EST by Susan Allen on behalf of Institute for Molecular Bioscience