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

• Published in: European journal of human genetics : EJHG Vol. 23; no. 4; pp. 486 - 493
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-04-2015
• Subjects: Adult; Animals; Bioinformatics; Cell Line; Cercopithecus aethiops; Child; Chromosome 9; Chromosome deletion; Chromosomes, Human, Pair 9 - genetics; Clonal deletion; Computational Biology; COS Cells; Disorders of Sex Development - genetics; Endocrinology; Etiology; Exome; Female; Gene Deletion; Gene expression; Genetic Linkage; Genetic Variation; Genetics; Genitalia; Genome-Wide Association Study; Genomics; Genotype; Genotype & phenotype; Genotypes; Gonads; HEK293 Cells; Hospitals; Humans; Kinases; Ligands; Linkage analysis; Male; Medical research; Mice; Mutation; Patients; Pedigree; Phenotype; Phenotypes; Plasmids - genetics; Primary Ovarian Insufficiency - genetics; Protein Conformation; Proteins; Steroidogenesis; Steroidogenic Factor 1 - genetics; Young Adult; Australia; Netherlands
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2014.130

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.