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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.
PMID
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Authors

Mayor MeshTerms
Keywords

Perrault syndrome

low frequency hearing loss

primary ovarian insufficiency

sensorineural hearing loss

Journal Title clinical genetics
Publication Year Start




PMID- 26970254
OWN - NLM
STAT- MEDLINE
DA  - 20160312
DCOM- 20170626
LR  - 20170626
IS  - 1399-0004 (Electronic)
IS  - 0009-9163 (Linking)
VI  - 91
IP  - 2
DP  - 2017 Feb
TI  - Expanding the genotypic spectrum of Perrault syndrome.
PG  - 302-312
LID - 10.1111/cge.12776 [doi]
AB  - 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.
CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Demain, L A M
AU  - Demain LA
AUID- ORCID: http://orcid.org/0000-0001-8694-7710
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - Urquhart, J E
AU  - Urquhart JE
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - O'Sullivan, J
AU  - O'Sullivan J
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - Williams, S G
AU  - Williams SG
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - Bhaskar, S S
AU  - Bhaskar SS
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - Jenkinson, E M
AU  - Jenkinson EM
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
FAU - Lourenco, C M
AU  - Lourenco CM
AD  - Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
FAU - Heiberg, A
AU  - Heiberg A
AD  - Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
FAU - Pearce, S H
AU  - Pearce SH
AD  - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; and
      Endocrine Department, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK.
FAU - Shalev, S A
AU  - Shalev SA
AD  - The Institute for Genetics, Ha'Emek Medical Centre, Afula, Israel.
AD  - Rapapport faculty of Medicine, Technion Haifa, Haifa, Israel.
FAU - Yue, W W
AU  - Yue WW
AD  - Structural Genomics Consortium, Nuffield Department of Clinical Medicine,
      University of Oxford, Oxford, UK.
FAU - Mackinnon, S
AU  - Mackinnon S
AD  - Structural Genomics Consortium, Nuffield Department of Clinical Medicine,
      University of Oxford, Oxford, UK.
FAU - Munro, K J
AU  - Munro KJ
AD  - School of Psychological Sciences, University of Manchester, Manchester, UK.
AD  - Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic
      Health Science Centre, Manchester, UK.
FAU - Newbury-Ecob, R
AU  - Newbury-Ecob R
AD  - Clinical Genetics, St Michaels Hospital, Bristol Genetics Laboratory Pathology
      Sciences, Southmead Hospital Bristol, Bristol, UK.
FAU - Becker, K
AU  - Becker K
AD  - Medical Genetics Center, Munich, Germany.
FAU - Kim, M J
AU  - Kim MJ
AD  - Department of Obstetrics and Gynecology, The Catholic University of Korea, Seoul,
      Korea.
FAU - O' Keefe, R T
AU  - O' Keefe RT
AD  - Faculty of Life Sciences, University of Manchester, Manchester, UK.
FAU - Newman, W G
AU  - Newman WG
AD  - Manchester Centre for Genomic Medicine, Institute of Human Development,
      University of Manchester, Manchester, UK.
AD  - Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic
      Health Science Centre, Manchester, UK.
LA  - eng
PT  - Journal Article
DEP - 20160401
PL  - Denmark
TA  - Clin Genet
JT  - Clinical genetics
JID - 0253664
RN  - 0 (Mitochondrial Proteins)
RN  - EC 3.4.21.92 (ClpP protein, human)
RN  - EC 3.4.21.92 (Endopeptidase Clp)
RN  - EC 3.6.4.- (DNA Helicases)
RN  - EC 3.6.4.12 (C10ORF2 protein, human)
RN  - EC 4.2.1.107 (Peroxisomal Multifunctional Protein-2)
RN  - EC 4.2.1.119 (HSD17B4 protein, human)
RN  - EC 6.1.1.- (Amino Acyl-tRNA Synthetases)
RN  - EC 6.1.1.4 (LARS2 protein, human)
RN  - Gonadal dysgenesis XX type deafness
SB  - IM
MH  - Amino Acyl-tRNA Synthetases/*genetics
MH  - DNA Helicases/*genetics
MH  - Endopeptidase Clp/*genetics
MH  - Exome/genetics
MH  - Female
MH  - Genotype
MH  - Gonadal Dysgenesis, 46,XX/*genetics/pathology
MH  - Hearing Loss, Sensorineural/*genetics/pathology
MH  - Homozygote
MH  - Humans
MH  - Male
MH  - Mitochondrial Proteins/*genetics
MH  - Mutation
MH  - Pedigree
MH  - Peroxisomal Multifunctional Protein-2/*genetics
MH  - Phenotype
MH  - Primary Ovarian Insufficiency/genetics/physiopathology
OTO - NOTNLM
OT  - Perrault syndrome
OT  - low frequency hearing loss
OT  - primary ovarian insufficiency
OT  - sensorineural hearing loss
EDAT- 2016/03/13 06:00
MHDA- 2017/06/27 06:00
CRDT- 2016/03/13 06:00
PHST- 2015/12/21 [received]
PHST- 2016/03/07 [revised]
PHST- 2016/03/07 [accepted]
AID - 10.1111/cge.12776 [doi]
PST - ppublish
SO  - Clin Genet. 2017 Feb;91(2):302-312. doi: 10.1111/cge.12776. Epub 2016 Apr 1.