PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene

Eur J Med Genet. 2020 Feb;63(2):103660. doi: 10.1016/j.ejmg.2019.04.017. Epub 2019 Apr 29.

Abstract

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

Keywords: Epileptic encephalopathy; PEHO syndrome; ZNHIT3 gene.

Publication types

  • Case Reports

MeSH terms

  • Brain Edema / congenital
  • Brain Edema / diagnosis*
  • Brain Edema / diagnostic imaging
  • Brain Edema / genetics*
  • Databases, Genetic
  • Edema / genetics
  • Epileptic Syndromes / genetics
  • Exome Sequencing
  • Female
  • Finland
  • Heterozygote
  • Humans
  • Infant, Newborn
  • Mutation, Missense
  • Neurodegenerative Diseases / congenital
  • Neurodegenerative Diseases / diagnosis*
  • Neurodegenerative Diseases / diagnostic imaging
  • Neurodegenerative Diseases / genetics*
  • Nuclear Proteins / genetics*
  • Optic Atrophy / congenital
  • Optic Atrophy / diagnosis*
  • Optic Atrophy / diagnostic imaging
  • Optic Atrophy / genetics*
  • Phenotype
  • Spasms, Infantile / congenital
  • Spasms, Infantile / diagnosis*
  • Spasms, Infantile / diagnostic imaging
  • Spasms, Infantile / genetics*
  • Transcription Factors / genetics*
  • Whole Genome Sequencing

Substances

  • Nuclear Proteins
  • Transcription Factors
  • ZNHIT3 protein, human

Supplementary concepts

  • PEHO syndrome