Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis

Alessia Catania, Anna Ardissone, Daniela Verrigni, Andrea Legati, Aurelio Reyes, Eleonora Lamantea, Daria Diodato, Davide Tonduti, Valentina Imperatore, Anna Maria Pinto, Isabella Moroni, Enrico Bertini, Alan Robinson, Rosalba Carrozzo, Massimo Zeviani, Daniele Ghezzi

Research output: Contribution to journalArticlepeer-review

Abstract

Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.

Original languageEnglish
Pages (from-to)563-568
Number of pages6
JournalJournal of Human Genetics
Volume63
Issue number5
DOIs
Publication statusPublished - May 2018

Keywords

  • Alleles
  • Child
  • Child, Preschool
  • Female
  • Fibroblasts/metabolism
  • Gene Expression
  • Haplotypes
  • Heterozygote
  • Humans
  • Infant
  • Introns
  • Leigh Disease/diagnosis
  • Lymphocytes/metabolism
  • Magnetic Resonance Imaging/methods
  • Male
  • Mitochondrial Proteins
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • RNA, Messenger/genetics
  • Whole Exome Sequencing

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