Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

Two TECPR2 VUS in trans confirmed pathogenic by long-read + multi-omics

A teenage girl with syndromic intellectual disability and neuromuscular abnormalities underwent trio exome, RNA-seq transcriptomics, and muscle proteomics. Trio exome identified two heterozygous TECPR2 variants (c.480G>A and c.2846C>A), initially classified as VUS. Long-read sequencing confirmed both variants in trans. Functional studies validated pathogenicity through expression (RNA-seq) and function (proteomics) abnormalities, enabling reclassification and definitive diagnosis, illustrating the value of integrated multi-omic diagnosis for ultra-rare gene VUS.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This case demonstrates the practical value of long-read sequencing for phasing two heterozygous variants and multi-omics for confirming pathogenicity without family segregation data. For TECPR2, a very rare and poorly characterized gene, these tools resolve cases that would otherwise remain in diagnostic odyssey indefinitely.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 1/2 · Sample size: 0/1 · Journal quality: 0/1 → Total: 5/10