Premium
Single‐fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases
Author(s) -
Zereg Elamine,
Chaussenot Annabelle,
Morel Godelieve,
Bannwarth Sylvie,
Sacconi Sabrina,
Soriani MarieHélène,
Attarian Shahram,
Cano Aline,
Pouget Jean,
Bellance Rémi,
Tranchant Christine,
Lannes Béatrice,
Paula André Maues,
Saadi AitElMkadem Samira,
Chafino Bernadette,
Berthet Mathieu,
Fragaki Konstantina,
PaquisFlucklinger Véronique,
Rouzier Cécile
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24037
Subject(s) - heteroplasmy , biology , mitochondrial dna , genetics , pathogenicity , mitochondrial disease , dna sequencing , phenotype , human mitochondrial genetics , computational biology , dna , gene , microbiology and biotechnology
Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as “definitely pathogenic” (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain “possibly pathogenic” (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as “definitely pathogenic.” We also illustrate the contribution of single‐fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy.