title: Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome.
abstract: Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co-segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c.1453_1454delGA, p.(Glu485Lysfs*5)) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin-like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.|National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: R
authors.initials: R
authors.lastname: Faridi
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: Genomics and Computational Biology Core, NIDCD, NIH, Bethesda, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Morell
authors.affiliation: Internal Medicine Consult Service, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Friedman
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.
authors.forename: L
authors.identifier: 0000-0001-8694-7710
authors.initials: L
authors.lastname: Demain
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: S
authors.initials: S
authors.lastname: Zahra
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: A A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.|Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: D
authors.initials: D
authors.lastname: Tohlob
authors.affiliation: Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.|Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan, Institute of Medical Sciences, Islamabad, Pakistan.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Assir
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Beaman
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: S N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.
authors.forename: W G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan, Institute of Medical Sciences, Islamabad, Pakistan.|Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan.
authors.forename: S
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D057167:Claudins / Q000235:genetics*; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree
chemical_list: D018797:Cell Cycle Proteins; D057167:Claudins; C510590:SGO2 protein, human; C422064:claudin 14
keywords: CLDN14; Perrault syndrome; SGO2; Sgol2a; Shugoshin-2; cohesin; coincidental syndrome; infertility; ovarian insufficiency