title: Expanding the genotypic spectrum of Perrault syndrome.
abstract: Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: L A M
authors.identifier: 0000-0001-8694-7710
authors.initials: LA
authors.lastname: Demain
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: S G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: S S
authors.initials: SS
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Jenkinson
authors.affiliation: Clinics Hospital of Ribeirao Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: C M
authors.initials: CM
authors.lastname: Lourenco
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Heiberg
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; and Endocrine Department, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
authors.affiliation: The Institute for Genetics, Ha'Emek Medical Centre, Afula, Israel.|Rapapport faculty of Medicine, Technion Haifa, Haifa, Israel.
authors.forename: S A
authors.initials: SA
authors.lastname: Shalev
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: W W
authors.initials: WW
authors.lastname: Yue
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mackinnon
authors.affiliation: School of Psychological Sciences, University of Manchester, Manchester, UK.|Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Munro
authors.affiliation: Clinical Genetics, St Michaels Hospital, Bristol Genetics Laboratory Pathology Sciences, Southmead Hospital Bristol, Bristol, UK.
authors.forename: R
authors.initials: R
authors.lastname: Newbury-Ecob
authors.affiliation: Medical Genetics Center, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Becker
authors.affiliation: Department of Obstetrics and Gynecology, The Catholic University of Korea, Seoul, Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: R T
authors.initials: RT
authors.lastname: O' Keefe
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.|Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: W G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D049071:Endopeptidase Clp / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D005838:Genotype; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics*; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000235:genetics / Q000503:physiopathology
chemical_list: D024101:Mitochondrial Proteins; C568646:ClpP protein, human; D049071:Endopeptidase Clp; D004265:DNA Helicases; C431576:TWNK protein, human; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D000604:Amino Acyl-tRNA Synthetases; C549096:LARS2 protein, human
keywords: Perrault syndrome; low frequency hearing loss; primary ovarian insufficiency; sensorineural hearing loss