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

doi:10.1038/s10038-018-0423-1

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 journal › Article › peer-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 language	English
Pages (from-to)	563-568
Number of pages	6
Journal	Journal of Human Genetics
Volume	63
Issue number	5
DOIs	https://doi.org/10.1038/s10038-018-0423-1
Publication status	Published - 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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Catania, A., Ardissone, A., Verrigni, D., Legati, A., Reyes, A., Lamantea, E., Diodato, D., Tonduti, D., Imperatore, V., Pinto, A. M., Moroni, I., Bertini, E., Robinson, A., Carrozzo, R., Zeviani, M., & Ghezzi, D. (2018). Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. Journal of Human Genetics, 63(5), 563-568. https://doi.org/10.1038/s10038-018-0423-1

Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. / Catania, Alessia; Ardissone, Anna; Verrigni, Daniela; Legati, Andrea; Reyes, Aurelio; Lamantea, Eleonora; Diodato, Daria; Tonduti, Davide; Imperatore, Valentina; Pinto, Anna Maria; Moroni, Isabella ; Bertini, Enrico; Robinson, Alan; Carrozzo, Rosalba; Zeviani, Massimo; Ghezzi, Daniele.

In: Journal of Human Genetics, Vol. 63, No. 5, 05.2018, p. 563-568.

Research output: Contribution to journal › Article › peer-review

Catania, A, Ardissone, A, Verrigni, D, Legati, A, Reyes, A, Lamantea, E, Diodato, D, Tonduti, D, Imperatore, V, Pinto, AM, Moroni, I , Bertini, E, Robinson, A, Carrozzo, R, Zeviani, M & Ghezzi, D 2018, 'Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis', Journal of Human Genetics, vol. 63, no. 5, pp. 563-568. https://doi.org/10.1038/s10038-018-0423-1

Catania, Alessia ; Ardissone, Anna ; Verrigni, Daniela ; Legati, Andrea ; Reyes, Aurelio ; Lamantea, Eleonora ; Diodato, Daria ; Tonduti, Davide ; Imperatore, Valentina ; Pinto, Anna Maria ; Moroni, Isabella ; Bertini, Enrico ; Robinson, Alan ; Carrozzo, Rosalba ; Zeviani, Massimo ; Ghezzi, Daniele. / Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. In: Journal of Human Genetics. 2018 ; Vol. 63, No. 5. pp. 563-568.

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title = "Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis",

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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AU - Catania, Alessia

AU - Ardissone, Anna

AU - Verrigni, Daniela

AU - Legati, Andrea

AU - Reyes, Aurelio

AU - Lamantea, Eleonora

AU - Diodato, Daria

AU - Tonduti, Davide

AU - Imperatore, Valentina

AU - Pinto, Anna Maria

AU - Moroni, Isabella

AU - Bertini, Enrico

AU - Robinson, Alan

AU - Carrozzo, Rosalba

AU - Zeviani, Massimo

AU - Ghezzi, Daniele

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N2 - 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.

AB - 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.

KW - Alleles

KW - Child

KW - Child, Preschool

KW - Female

KW - Fibroblasts/metabolism

KW - Gene Expression

KW - Haplotypes

KW - Heterozygote

KW - Humans

KW - Infant

KW - Introns

KW - Leigh Disease/diagnosis

KW - Lymphocytes/metabolism

KW - Magnetic Resonance Imaging/methods

KW - Male

KW - Mitochondrial Proteins

KW - Mutation, Missense

KW - Pedigree

KW - Phenotype

KW - RNA, Messenger/genetics

KW - Whole Exome Sequencing

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