An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature

Hum Mutat. 2016 Dec;37(12):1354-1362. doi: 10.1002/humu.23120. Epub 2016 Oct 7.


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.

Keywords: C10orf2; CLPP; HARS2; HSD17B4; LARS2; NGS; Perrault syndrome.

Publication types

  • Review

MeSH terms

  • Adolescent
  • Amino Acyl-tRNA Synthetases / genetics
  • Child
  • Child, Preschool
  • DNA Helicases / genetics
  • Endopeptidase Clp / genetics
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Gonadal Dysgenesis, 46,XX / genetics*
  • Hearing Loss, Sensorineural / genetics*
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Mitochondrial Proteins / genetics
  • Mutation, Missense*
  • Pedigree
  • Peroxisomal Multifunctional Protein-2 / genetics
  • Sequence Analysis, DNA / methods*


  • Mitochondrial Proteins
  • ClpP protein, human
  • Endopeptidase Clp
  • DNA Helicases
  • TWNK protein, human
  • Peroxisomal Multifunctional Protein-2
  • HSD17B4 protein, human
  • Amino Acyl-tRNA Synthetases
  • HARS2 protein, human

Supplementary concepts

  • Gonadal dysgenesis XX type deafness