Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy

Abstract

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

“…Both heterozygous and homozygous disease-causing variants in several ARS genes have been reported 11 . Biallelic damaging variants in ARS2 genes, encoding mitochondriallocalized enzymes, tend to cause mitochondrial encephalopathies, whereas biallelic damaging variants in ARS1 genes, encoding cytoplasm-localized enzymes, tend to cause epileptic encephalopathies or other systemic conditions 3,4,[12][13][14][15] . Interestingly, certain variants in ARS genes show peripheral neuropathy (i.e., Charcot-Marie-Tooth syndrome) with dominant inheritance, at least partially explained by toxic gain-of-function effects of mutant proteins binding to neuropilin-2 [16][17][18][19][20][21][22] .…”

“…Mutations in genes involved in centriolar biogenesis/assembly (MCPH), microtubule regulation (TUB genes), DNA damage (PNKP), signaling pathways (ALFY/ASPM), transcription and metabolism are linked to microcephaly [29][30][31][32][33][34][35] . Recently, QARS, KARS, VARS, and CARS ARS family genes were implicated in microcephaly, but mammalian model systems and mechanisms remain unexplored 3,4,11,36,37 .…”

Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy

“…[27][28][29][30] For example, defects in genes encoding aminoacyl-tRNA synthetases cause a variety of phenotypes, ranging from hypomyelination to brain malformations. [31][32][33][34][35][36][37][38] Given the broad clinical spectrum of phenotypes associated with POLR3 deficiency, it is clear that pathogenic variants in POLR3 genes have distinct effects on various cellular processes. 25,39 Variants in POLR3A have been associated with phenotypes ranging from spastic ataxia-related disorders to neonatal progeroid syndrome, whereas variants in POLR3B have been associated with isolated hypogonadotropic hypogonadism, without hypomyelination or hypodontia, and a distinct phenotype of cerebellar hypoplasia with endosteal sclerosis.…”

Matching whole genomes to rare genetic disorders: Identification of potential causative variants using phenotype‐weighted knowledge in the CAGI SickKids5 clinical genomes challenge

“…There is a number of possible explanations for the low yield of diagnostic variants, even given whole‐genome sequencing data. We conclude by considering the most relevant of these, and the prospects for progress: New genes related to specific disease phenotypes are continually being discovered (Friedman et al, ; Guelfi et al, ) implying that there are many more still to be found. A strategy that might help address this problem is to consider all putative impact variants in all genes, and see if any of these genes have phenotype descriptions that offer some clue to a possible match (a genotype to phenotype approach; Hu et al, ; Wang et al, ).…”