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

TitleCompound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.
Publication TypeJournal Article
Year of Publication2018
AuthorsCatania, A, Ardissone, A, Verrigni, D, Legati, A, Reyes, A, Lamantea, E, Diodato, D, Tonduti, D, Imperatore, V, Pinto, AMaria, Moroni, I, Bertini, E, Robinson, AJ, Carrozzo, R, Zeviani, M, Ghezzi, D
JournalJ Hum Genet
Volume63
Issue5
Pagination563-568
Date Published2018 May
ISSN1435-232X
KeywordsAlleles, Child, Child, Preschool, Female, Fibroblasts, Gene Expression, Haplotypes, Heterozygote, Humans, Infant, Introns, Leigh Disease, Lymphocytes, Magnetic Resonance Imaging, Male, Mitochondrial Proteins, Mutation, Missense, Pedigree, Phenotype, RNA, Messenger, Whole Exome Sequencing
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.

DOI10.1038/s10038-018-0423-1
Alternate JournalJ. Hum. Genet.
Citation Key10.1038/s10038-018-0423-1
PubMed ID29531337
PubMed Central IDPMC6071912
Grant List322424 / / European Research Council / International