title: STAG3 truncating variant as the cause of primary ovarian insufficiency.
abstract: Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI.
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Polona
authors.initials: P
authors.lastname: Le Quesne Stabej
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Hywel J
authors.initials: HJ
authors.lastname: Williams
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Chela
authors.initials: C
authors.lastname: James
authors.affiliation: Division of Medicine, UCL, London, UK.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Tekman
authors.affiliation: Division of Medicine, UCL, London, UK.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.|Division of Medicine, UCL, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.affiliation: Department of Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Reproductive Medicine Unit, Institute for Women's Health, University College London Hospitals, London, UK.
authors.forename: Gerard S
authors.initials: GS
authors.lastname: Conway
mesh_terms: D000293:Adolescent; D000568:Amenorrhea / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002648:Child; D002897:Chromosomes, Human, Pair 7; D003241:Consanguinity; D059472:Exome; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D035781:Siblings
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C406153:STAG3 protein, human