Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

Hum Genet. 2020 Oct;139(10):1325-1343. doi: 10.1007/s00439-020-02176-w. Epub 2020 May 12.

Abstract

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • Adolescent
  • Adult
  • Amino Acyl-tRNA Synthetases / genetics*
  • Base Sequence
  • Child
  • DNA, Mitochondrial / genetics
  • DNA-Binding Proteins / genetics*
  • Dimethylallyltranstransferase / genetics*
  • Endopeptidase Clp / genetics*
  • Farnesyltranstransferase / genetics*
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease*
  • Geranyltranstransferase / genetics*
  • Gonadal Dysgenesis, 46,XX / diagnosis
  • Gonadal Dysgenesis, 46,XX / genetics*
  • Gonadal Dysgenesis, 46,XX / pathology
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mitochondrial Proteins / genetics*
  • Ovary / metabolism
  • Ovary / pathology
  • Pedigree
  • Peroxisomes / metabolism
  • Peroxisomes / pathology
  • Transcription Factors / genetics*

Substances

  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • TFAM protein, human
  • Transcription Factors
  • Dimethylallyltranstransferase
  • Geranyltranstransferase
  • Farnesyltranstransferase
  • GGPS1 protein, human
  • ClpP protein, human
  • Endopeptidase Clp
  • ATPases Associated with Diverse Cellular Activities
  • PEX6 protein, human
  • Amino Acyl-tRNA Synthetases
  • LARS2 protein, human

Supplementary concepts

  • Gonadal dysgenesis XX type deafness