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. 2024 Feb 23:12:1331351.
doi: 10.3389/fcell.2024.1331351. eCollection 2024.

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

C Nogueira #  1   2 , C Pereira #  2 , L Silva  1   2 , Mateus Laranjeira  1 , A Lopes  2 , R Neiva  2 , E Rodrigues  3 , T Campos  3 , E Martins  4 , A Bandeira  4 , M Coelho  4 , M Magalhães  5 , J Damásio  5 , A Gaspar  6 , P Janeiro  6 , A Levy Gomes  7 , A C Ferreira  8 , S Jacinto  8 , J P Vieira  8 , L Diogo  9 , H Santos  10 , C Mendonça  11 , L Vilarinho  1   2
Affiliations

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

C Nogueira et al. Front Cell Dev Biol. .

Abstract

Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients. Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA. Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing. Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options.

Keywords: mitochondrial DNA; mitochondrial diseases; next-generation sequencing; nuclear DNA; nuclear genes; oxidative phosphorylation; respiratory chain.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Affected systems at disease onset in our cohort.
FIGURE 2
FIGURE 2
Distribution of the nDNA pathogenic/probably pathogenic variants by the affected genes according to their functional groups.
FIGURE 3
FIGURE 3
Distribution of the nDNA VUS by the affected genes according to their functional groups.
FIGURE 4
FIGURE 4
Localization and size of mtDNA large-scale deletions identified in this study.
FIGURE 5
FIGURE 5
Distribution of the pathogenic/likely pathogenic variants through the mtDNA genes according to their functional groups.
FIGURE 6
FIGURE 6
Distribution of VUS through the mtDNA genes according to their groups.
FIGURE 7
FIGURE 7
Molecular results of deceased patients.
FIGURE 8
FIGURE 8
Diagnostic algorithm for a suspicion of mitochondrial disease.
FIGURE 9
FIGURE 9
Physical network of genetic interactions associated with the DARS2 gene. Adapted from the STRING platform (https://string-db.org/).
See this image and copyright information in PMC

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