Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort
Abstract
Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.
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BibTeX
@article{gouiza2026integrated,
title = {{Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort}},
author = {Ismail Gouiza and Aymane Bouzidi and Meriem Hechmi and Majida Charif and Abir Zioudi and Nadia Kheriji and Hela Boudabous and Mouna Zribi and Safa Khatrouch and Raoudha Kebaili and Ilhem Ben Youssef-Turki and Mediha Trabelsi and Slim Abdelmoula and Ichraf Kraoua and Amel Ben Chehida and Rym Kefi and Guy Lenaers},
journal = {Mitochondrion},
year = {2026},
month = oct,
doi = {10.1016/j.mito.2026.102195},
url = {https://hal.science/hal-05804321v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort
AU - Ismail Gouiza
AU - Aymane Bouzidi
AU - Meriem Hechmi
AU - Majida Charif
AU - Abir Zioudi
AU - Nadia Kheriji
AU - Hela Boudabous
AU - Mouna Zribi
AU - Safa Khatrouch
AU - Raoudha Kebaili
AU - Ilhem Ben Youssef-Turki
AU - Mediha Trabelsi
AU - Slim Abdelmoula
AU - Ichraf Kraoua
AU - Amel Ben Chehida
AU - Rym Kefi
AU - Guy Lenaers
PY - 2026
DA - 2026/10/17
JO - Mitochondrion
DO - 10.1016/j.mito.2026.102195
UR - https://hal.science/hal-05804321v1
AB - Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.
SN - 1567-7249
SN - 1872-8278
ER -