A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies

Abstract

Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

“…To date, 26 patients are reported with LTBL (12 by Steenweg et al (2012), one by Talim et al (2013), two by Taylor et al (2014), one by Biancheri et al (2015), one by Kohda et al (2016), one by Kevelam et al (2016), one by Danhauser et al (2016), one by Taskin et al (2016), one by G€ ung€ or et al (2016), two by Şahin et al (2016) and two by Pronicka et al (2016)), with our patient being the 26th reported patient. The phenotype of our patient fits the severe group of LTBL patients, mostly due to signs of perinatal presentation of the disease and rapid decline of her clinical status.…”

“…The fifth patient from Taskin et al (2016) had a homozygous c.322C>T (p.Arg108Trp) missense change and presented a mild phenotype. Compound heterozygous changes were identified in three additional patients as part of large-scale WES studies but without specific details of phenotypes for comparison (Kohda et al 2016;Pronicka et al 2016). Regarding the two heterozygous variants in our patient, the start-loss p.Met1?…”

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

“…Mutations affecting mitochondrial translation machinery have often been associated with liver dysfunction. 8,11,58 The observed differences in presentation between individual patients and the mouse model may reflect the importance of both the location and severity of the mutation (including hypomorphic versus loss-of-function alleles) as well as the genetic background. This consideration is also relevant to the observed differences in both onset and progression of clinical disease between the different MRPS34 human subjects.…”

“…14 Disorders caused by mutations in mitoribosomal proteins are clinically heterogeneous and multi-systemic, with common features including neurodevelopmental disabilities, brain abnormalities, liver disease, kidney disease, cardiomyopathy, and lactic acidosis. 11,15 They generally lead to death in infancy or early childhood, 15 although survival into teenage years and adulthood has been reported. 8,14,16 The small number of mitoribosomal genes known to underlie OXPHOS diseases is surprising, since nearly two-thirds of mitoribosomal genes are essential for OXPHOS based on a highthroughput knock-out death screen in cell models.…”

Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes

“…The diagnosis of disorders of CIII-deficiency is challenging as they comprise a group of rare conditions that have vastly different phenotypes. The advent of whole-exome sequencing has also facilitated the molecular diagnosis of these rare disorders (Kohda et al 2016).…”