Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Dahl H-H. Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. Am J Hum Genet. 1998;63:1594–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    McKenzie M, Tucker EJ, Compton AG, Lazarou M, George C, Thorburn DR, Ryan MT. Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. J Mol Biol. 2011;414:413–26.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong S-E, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kohda M, Tokuzawa Y, Kishita Y, Nyuzuki H, Moriyama Y, Mizuno Y, et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 2016;12:e1005679.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Fang F, Liu Z, Fang H, Wu J, Shen D, Sun S, et al. The clinical and genetic characteristics in children with mitochondrial disease in China. Sci China Life Sci. 2017;60:746–57.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K, Matsunaga A, et al. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis. 2017;40:685–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bianciardi L, Imperatore V, Fernandez-Vizarra E, Lopomo A, Falabella M, Furini S, et al. Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene. Molec Genet Metab. 2016;119:214–22.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Legati A, Reyes A, Nasca A, Invernizzi F, Lamantea E, Tiranti V, et al. New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochim Biophys Acta. 2016;1857:1326–35.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Telethon Grant GGP15041; the Pierfranco and Luisa Mariani Foundation (to DG); the MRC-QQR (2015-2020) grant; the ERC advanced grant FP7-322424, the NRJ-Institut de France grant (to MZ); the Italian Ministry of Health (Ricerca Corrente 2016-2017 to DG, EB, and RC). The “Cell lines and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases” of the Telethon Network of Genetic Biobanks (grant GTB12001J) and the EuroBioBank Network supplied biological specimens.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Daniele Ghezzi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Catania, A., Ardissone, A., Verrigni, D. et al. Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. J Hum Genet 63, 563–568 (2018). https://doi.org/10.1038/s10038-018-0423-1

Download citation

Further reading

Search

Quick links