WARS2 – Mitochondrial disease

The mitochondrial tryptophanyl-tRNA synthetase gene WARS2 encodes an essential enzyme for mitochondrial translation. Biallelic WARS2 variants have been robustly linked to autosomal recessive mitochondrial disease (PMID:28905505). Affected individuals present with neurodevelopmental impairment, leukoencephalopathy, growth retardation, and a spectrum of movement disorders, with respiratory chain defects often confined to neural tissue.

Genetic evidence includes 19 probands from 15 unrelated families: six individuals from five families with neonatal to attenuated onset encephalopathy (PMID:28905505), two siblings with progressive leukoencephalopathy (PMID:30920170), six novel cases of dopa-responsive parkinsonism and myoclonus-ataxia (PMID:34890876), four additional patients sharing a recurrent hypomorphic allele (PMID:37107582), and one adult dystonia case (PMID:39073549). All demonstrate biallelic segregation consistent with autosomal recessive inheritance.

The variant spectrum comprises at least 11 distinct missense changes (e.g., c.833T>G (p.Val278Gly)) and 8 predicted loss-of-function alleles, including nonsense, frameshift, and canonical splice variants. A recurrent hypomorphic missense variant, p.Trp13Gly (gnomAD MAF ~0.5%), frequently occurs in trans with truncating alleles and correlates with milder, later-onset phenotypes (PMID:37107582).

Segregation analysis across sibships confirms co-segregation of compound heterozygous and homozygous genotypes in affected individuals, with no evidence for dominant transmission or phenotypic heterogeneity within families. At least two affected siblings have been reported in a single pedigree, reinforcing recessive inheritance (PMID:30920170).

Functional studies in patient-derived neuroepithelial stem cells reveal combined complex I and IV deficiencies, increased uncharged mitochondrial tRNATrp, and reduced WARS2 protein levels (PMID:28905505). Yeast complementation assays show that missense alleles markedly impair oxidative growth and mitochondrial translation, and Drosophila WARS2 silencing causes lethality, confirming a loss-of-function mechanism (PMID:30920170, PMID:39230874).

No conflicting reports have refuted this association. The collective genetic and experimental data satisfy ClinGen criteria for a Strong gene–disease relationship. Key take-home: Biallelic WARS2 variants cause a clinically recognizable autosomal recessive mitochondrial disease, supporting their inclusion in diagnostic gene panels and guiding functional assays for variant interpretation.

References

• Human mutation • 2017 • Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. PMID:28905505
• Molecular genetics & genomic medicine • 2019 • Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy. PMID:30920170
• Parkinsonism & related disorders • 2022 • WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia. PMID:34890876
• Genes • 2023 • The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant. PMID:37107582
• Cerebellum (London, England) • 2024 • Compound Heterozygous WARS2 Variants Including a Hypomorphic Allele Cause a Milder Phenotype of Complex Dopa Responsive Dystonia: Case Report and Review of the Literature. PMID:39073549
• Human molecular genetics • 2024 • Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases. PMID:39230874

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