Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta

Background Intellectual disability is a complex multi‐faceted condition with diverse underlying etiologies. One rare form of intellectual disability is secondary to the loss of TRAPPC9, an activator of NF‐κB and a mediator of intracellular protein processing and trafficking. TRAPPC9 deficiency has been described in 48 patients with more than 15 pathologic variants. Method Clinical evaluation, magnetic resonance imaging, and whole‐exome sequencing were used to characterize the underlying cause of absent speech, restricted/repetitive behaviors, and worsening behavioral outbursts in 27‐year‐old man from Malta. Results Magnetic Resonance Imaging showed morphologic abnormalities, including global cerebral and cerebellar hypoplasia. Genetic analysis through Whole Exome Sequencing identified a homozygous deletion (c.568_574del) in TRAPPC9 resulting in a frameshift, premature stop codon, and ultimately a truncated protein (p.Trp190Argfs*95). In this case, the pathogenic variant was homozygous, identified in both of the parents without known consanguinity. Conclusion Given the phenotype and genotype consistent with a deficiency in TRAPPC9, it is likely that this patient represents a novel case of this rare genetic syndrome. Specifically, this case, in the context of 48 total reported patients, raises questions as to the geographic origin of the pathologic variant and optimal detection and therapeutic intervention for this condition. A man previously diagnosed with autism spectrum disorder secondary to intellectual disability, absent speech and repetitive behaviors was found to have homozygous pathogenic variants in TRAPPC9. In the context of the currently reported 48 known cases of TRAPPC9 pathogenic variants, his phenotype is consistent with previously reported phenotypes. Interestingly, it is found that, although the known pathogenic variants do not cluster in respect to location within the gene, the known cases all appears to be from a localized geographic area.