Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases

Abstract

Background Mitochondrial disease (MD) is genetically a heterogeneous group of disorders with impairment in respiratory chain complexes or pathways associated with the mitochondrial function. Nowadays, it is still a challenge for the genetic screening of MD due to heteroplasmy of mitochondrial genome and the complex model of inheritance. This study was designed to investigate the feasibility of whole exome sequencing (WES)‐based testing as an alternative option for the diagnosis of MD. Methods A Chinese Han cohort of 48 patients with suspect MD features was tested using nanoWES, which was a self‐designed WES technique that covered the complete mtDNA genome and 21,019 nuclear genes. Fourteen patients were identified with a single genetic variant and three with single deletion in mtDNA. Results The heteroplasmy levels of variants in mitochondrial genome range from 11% to 100%. NanoWES failed to identify multiple deletions in mtDNA compared with long range PCR and massively parallel sequencing (LR‐PCR/MPS). However, our testing showed obvious advantages in identifying variations in nuclear DNA. Based on nanoWES, we identified two patients with nuclear DNA variation. One of them showed Xp22.33‐q28 duplication, which indicated a possibility of Klinefelter syndrome. Conclusion NanoWES yielded a diagnostic rate of 35.4% for MD. With the rapid advances of next generation sequencing technique and decrease in cost, we recommend the usage of nanoWES as a first‐line method in clinical diagnosis.

Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly

“…In the most recent study conducted in China ( Wang et al, 2023 ), genetic causes were evaluated in 224 cases of prenatal microcephaly by CMA and WES. The positive diagnosis rate for WES (19.14%) was higher than both CMA and WES reported in other studies ( Petrovski et al, 2019 ; Al-Kouatly et al, 2021 ; Sun et al, 2022 ). It was also found that the diagnosis rate by CMA was not significantly different between syndromic and primary microcephaly.…”

Genetic diagnosis of fetal microcephaly at a single tertiary center in China

“…We found a positive diagnosis rate of 3.74% (7/187) for CMA, which was slightly lower than that reported in other studies ( von der Hagen et al, 2014 ) (14.94%). We also recorded a positive diagnosis rate of 19.14% (31/162) for ES, which was higher than CMA and the average diagnosis rate of ES reported in other studies (10%) ( Petrovski et al, 2019 ; Al-Kouatly et al, 2021 ; Sun et al, 2022 ). The rate was also slightly higher than that of the previous largest sample size of the microcephaly study, which recorded a positive diagnosis rate of 18.83% ( von der Hagen et al, 2014 ).…”

The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies

“…Given the abundance of mitochondrial DNA, it's deep sequencing is easily achieved by standard WGS, but the detection of pathogenic mitochondrial variants remains challenging due to the occurrence of heteroplasmy, which may result in a low aberrant read fraction, as well as complex rearrangements, which may only be detectable in muscular tissues (Macken et al, 2021). WES with targeted capture of the mitochondrial DNA has also been used to identify mitochondrial sequence variants and deletions (C. Sun et al, 2022) but a direct comparison to WGS is lacking.…”