TRAPPC9-Related Intellectual Developmental Disorder: A Systematic Review and a Novel Case of a Complex Structural Variant.

Background: Autosomal recessive intellectual developmental disorder-13 (MRT13; OMIM #613192) is a rare neurodevelopmental disorder caused by pathogenic variants in TRAPPC9. Most reported variants are single-nucleotide variants (SNVs), small insertions/deletions, or copy number variants (CNVs), whereas complex structural variants (SVs) remain poorly characterized. Objectives: This study sought to review the clinical and molecular spectrum of TRAPPC9-related disorder, harmonize reported variants, explore genotype-phenotype correlations, and expand the mutational spectrum by reporting a novel patient with a cryptic SV. Methods: We report a novel patient whose diagnostic workup included array-CGH, whole-exome sequencing, karyotyping, and optical genome mapping. Additionally, a systematic literature search was primarily conducted in PubMed/MEDLINE from 2009 to January 2026, with Embase, Web of Science, Google Scholar, Orphanet, OMIM, and ClinVar used as supplementary sources. Patients carrying pathogenic/likely pathogenic TRAPPC9 variants were included. Clinical and molecular data were extracted and descriptively summarized. Genotype-phenotype correlations were explored. Reported variants were re-annotated using MANE Select reference transcripts. Results: The reported patient showed biallelic TRAPPC9 disruption due to two independently inherited structural variants: a maternal ~35 kb intragenic deletion involving exons 10-12, identified by 400K array-CGH, and a paternal balanced translocation t(4;8) disrupting TRAPPC9 within intron 8, characterized by trio-OGM and paired-end whole-genome sequencing (PE-WGS). Thirty-one studies reporting 75 previously published patients were included in the literature review; together with the novel patient described here, the final cohort comprised 76 patients. Intellectual disability was present in 100% of cases, followed by brain MRI abnormalities (95.9%), microcephaly (82.3%), motor delay (71.4%), dysmorphic features (69.8%), obesity (52.8%), behavioral abnormalities/autism spectrum disorder (49.2%/43.8%), and epilepsy (15.9%). Most patients (84.2%) harbored homozygous variants. Thirty-two distinct sequence variants were identified, predominantly loss-of-function. CNVs were identified in 13.2% of patients. No genotype-phenotype correlations were identified. Conclusions: The systematic review provides an updated and harmonized overview of the clinical and molecular spectrum of TRAPPC9-related disorder, supporting the presence of a recognizable phenotype and confirming the predominance of loss-of-function variants. Our case further highlights the contribution of cryptic structural variants to the mutational spectrum of TRAPPC9 and the diagnostic value of advanced genomic approaches.