Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.
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Peer-reviewed
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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.
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Keywords
Alleles, 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, Exome Sequencing
Journal Title
J Hum Genet
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Journal ISSN
1434-5161
1435-232X
1435-232X
Volume Title
63
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Springer Science and Business Media LLC
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Sponsorship
Medical Research Council (MC_UP_1002/1)
European Research Council (322424)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_U105674181)
Medical Research Council (MC_UU_00015/7)
European Research Council (322424)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_U105674181)
Medical Research Council (MC_UU_00015/7)