title: An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature.
abstract: Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene.
authors.affiliation: Otorhinolaryngologie et chirurgie cervico-faciale, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Lerat
authors.affiliation: Laboratoire de Génétique Moléculaire, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Jonard
authors.affiliation: Otorhinolaryngologie pédiatrique, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Natalie
authors.initials: N
authors.lastname: Loundon
authors.affiliation: Endocrinologie, Hôpital Saint-Antoine, AP-HP, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire, Hôpital l'Archet, Nice, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rouzier
authors.affiliation: Génétique Médicale, Centre Hospitalier Universitaire, Hôpital Saint Jacques, Besançon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: Génétique Médicale, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Souad
authors.initials: S
authors.lastname: Gherbi
authors.affiliation: Otorhinolaryngologie pédiatrique, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Eréa-Nöel
authors.initials: EN
authors.lastname: Garabedian
authors.affiliation: Laboratoire de Génétique Moléculaire, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.affiliation: Endocrinologie et Médecine de la Reproduction, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Touraine
authors.affiliation: Otorhinolaryngologie et chirurgie cervico-faciale, Hôpital de la Pitié Salpétrière, AP-HP, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mosnier
authors.affiliation: Génétique Médicale, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Otorhinolaryngologie pédiatrique, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Denoyelle
authors.affiliation: Génétique Médicale, Centre de Référence des Surdités Génétiques, Hôpital Necker, AP-HP, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
mesh_terms: D000293:Adolescent; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D049071:Endopeptidase Clp / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D024101:Mitochondrial Proteins / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*
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; C093612:HARS2 protein, human
keywords: C10orf2; CLPP; HARS2; HSD17B4; LARS2; NGS; Perrault syndrome