# Correlation of MLASA2 Clinical Phenotype and Survival with Mt-TyrRS Protein Damage: Linking Systematic Review, Meta-Analysis and 3D Hotspot Mapping

## TL;DR

This study combines clinical data and protein structure analysis to understand how mutations in the YARS2 gene affect MLASA2 disease severity and survival.

## Contribution

The study introduces a novel framework integrating clinical, structural, and computational data to classify MLASA2 mutations by risk.

## Key findings

- Anemia, sideroblastic phenotype, and lactic acidosis are the most common clinical features in MLASA2.
- Survival rates decrease significantly with cardiomyopathy and early diagnosis.
- A 3D map of YARS2 mutations identifies high-risk clusters linked to disease severity.

## Abstract

Myopathy, Lactic Acidosis, and Sideroblastic Anemia type 2 (MLASA2) is a rare mitochondrial disorder caused by pathogenic variants (PVs) in the YARS2 gene (which encodes the Mt-TyrRS protein. We performed a comprehensive clinical–molecular synthesis by integrating a systematic review and meta-analysis of all published MLASA2 cases with survival modeling and three-dimensional structural mapping. Across the aggregated cohort, anemia (88.6%), sideroblastic phenotype (85.7%), and lactic acidosis (82.9%) were the most prevalent phenotypes. Fifteen PVs were identified, dominated by p.(Phe52Leu) (29.4%). Survival estimates were 94.1% at 10 years, 70.7% at 30 years, and 42.4% at 50 years; cardiomyopathy and diagnosis before age 10 were associated with decreased survival. We generated the first 3D structural map of all reported Mt-TyrRS PVs, identifying nine spatial hotspots across catalytic, anticodon-binding, and tRNA-binding domains. An integrated framework combining structural density, clinical severity, in silico predictions, and ΔΔG destabilization classified three clusters as High-risk, three as Medium-risk, and three as Low-risk. Among them, cluster 3, a large catalytic hotspot encompassing 44 residues and including nearly half of all MLASA2 cases, showed the strongest pathogenic convergence. This clinical–structural integration provides new insights for a better comprehension of MLASA2, enhancing variant interpretation and improving diagnostic and prognostic precision.