VARS2 – Combined Oxidative Phosphorylation Deficiency Type 20

Autosomal recessive variants in VARS2 underlie combined oxidative phosphorylation defect type 20, a severe early-onset mitochondrial encephalopathy. Affected individuals present in the neonatal period with hypotonia, microcephaly, feeding difficulties and lactic acidosis progressing to cardiomyopathy and refractory epilepsy.

Multiple case reports describe five independent probands including the first Portuguese case with a homozygous c.1100C>T (p.Thr367Ile) variant identified by exome sequencing in a child with fatal encephalopathy (PMID:29478218). A compound heterozygous c.1163C>T and c.1940C>T genotype was reported in a 3-year-old with microcephaly and seizures (PMID:36157797).

Broader cohorts include 13 patients from nine unrelated families with bi-allelic missense or splicing VARS2 variants causing combined Complex I + IV defects, all segregating in sibships and absent from population databases (PMID:29314548). Three additional individuals with neonatal encephalocardiomyopathy harbored compound heterozygous VARS2 alleles confirmed functionally in fibroblasts (PMID:27502409). A Chinese family case expanded the spectrum with c.643C>T (p.His215Tyr) and c.1354G>T (p.Met452Val) in a newborn with cardiomyopathy (PMID:30458719).

In total, at least 19 probands have been reported with 12 distinct missense and splice variants affecting conserved residues or canonical splice sites. Variants include homozygous and compound heterozygous c.1100C>T (p.Thr367Ile), c.643C>T (p.His215Tyr) and c.1354G>T (p.Met452Val). No recurrent founder alleles have been described; carrier frequencies are exceedingly rare (<0.001 in gnomAD).

Functional studies demonstrate loss of VARS2 protein and valyl-tRNA levels in patient fibroblasts with rescue upon wild-type transcript expression, yeast modeling of p.Thr367Ile confirming pathogenicity, and zebrafish morphants showing CNS and cardiac defects with integrated stress response activation (PMID:24827421; PMID:35806332). These data support a loss-of-function mechanism.

Collectively, autosomal recessive VARS2 variants cause a definitive mitochondrial synthetase disorder with consistent biochemical and clinical phenotypes. Exome sequencing should be considered early in infants with unexplained neonatal encephalopathy, cardiomyopathy and lactic acidosis. Key Take-home: VARS2 variant screening enables rapid diagnosis of COXPD20 guiding metabolic management and family planning.

References

• JIMD reports • 2018 • Mitochondrial Encephalopathy: First Portuguese Report of a VARS2 Causative Variant. PMID:29478218
• World journal of clinical cases • 2022 • VARS2 gene mutation leading to overall developmental delay in a child with epilepsy: A case report. PMID:36157797
• Human mutation • 2014 • VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. PMID:24827421
• Human genomics • 2017 • Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism. PMID:29137650
• Metabolic brain disease • 2017 • Neonatal encephalocardiomyopathy caused by mutations in VARS2. PMID:27502409
• BMC medical genetics • 2018 • A novel compound heterozygous mutation in VARS2 in a newborn with mitochondrial cardiomyopathy: a case report of a Chinese family. PMID:30458719
• Human mutation • 2018 • Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. PMID:29314548
• International journal of molecular sciences • 2022 • VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation. PMID:35806332

Evidence Based Scoring (AI generated)