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


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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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.

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Correspondence to Daniele Ghezzi.

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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).

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