Clinical Significance of mRNA Nonstop Decay in Rare Disease Diagnosis

• Nonstop decay (NSD) is a cellular surveillance mechanism that targets and degrades mRNAs lacking stop codons, preventing the translation of potentially harmful truncated proteins.
• Stop-loss variants, such as stop codon single nucleotide variants or frameshift variants upstream of the natural stop codon, can trigger NSD if no downstream compensatory stop codon is present before the poly-A tail.
• Despite the well-established functional importance of the NSD pathway, these variants currently are not included in the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) variant interpretation guidelines nor the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Workgroup’s PVS1 criterion recommendations, potentially leading to the underestimation of these pathogenic variants in the diagnosis of rare diseases.