Expanding the MRPS34 Genotype–Phenotype Correlation: Two Novel Cases and a Cohort Review

MRPS34 encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in MRPS34 cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with MRPS34-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic MRPS34 variants. A systematic review of all previously reported cases was performed to assess possible genotype–phenotype correlations (n = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T>C, p.(?)) and a nonsense variant (c.94C>T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G>A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G>A, p.(?) correlated with longer survival. MRPS34-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.