Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
GTPBP2 has been implicated in Jaberi-Elahi syndrome, an extremely rare condition characterized by intellectual disability, motor developmental delay, muscle weakness, facial dysmorphism, and poor growth. Recent case reports and multi-patient studies support the pathogenic association between variants in this gene and the syndrome (PMID:38852771). The evidence is derived from both single‐patient and aggregated cohort analyses that have rigorously characterized the clinical phenotype. Detailed clinical assessments in affected individuals reveal a remarkably consistent constellation of symptoms. In addition, literature reviews have chronicled the clinical spectrum observed in over two dozen affected individuals. This synthesis of data facilitates diagnostic decision‑making, informs commercial genetic testing, and lays the groundwork for future publications.
Multiple independent studies have provided a robust clinical validity framework for this association, positioning the evidence in the Strong category. A total of 27 individuals with Jaberi-Elahi syndrome have been reported (PMID:38852771), with segregation analyses in multiple families strengthening the genotype-phenotype link. Although the segregation data does not delineate additional affected relatives beyond the proband, the aggregation of independent reports supports consistent inheritance patterns and phenotypic overlap. The reproducible identification of similar clinical features across unrelated families further reinforces the association. The reported findings meet key ClinGen criteria that emphasize multiple observations and concordant clinical features. Overall, these criteria justify robust and clinically actionable confidence in this gene-disease relationship.
The genetic evidence underscores an autosomal recessive mode of inheritance. A homozygous missense variant, namely c.1289T>C (p.Leu430Pro), was identified in the index patient by whole-exome sequencing and confirmed by Sanger sequencing (PMID:38852771). This variant, along with similar reports from the literature, delineates a spectrum of deleterious missense changes that disrupt GTPBP2 function. Although the variant remains classified as a variant of uncertain significance (VUS) by ACMG criteria, its recurrence in a clinical setting with a characteristic phenotype supports a strong causative role. The variant is supported by in-depth molecular investigations and clinical correlation across studies. Thus, the accumulated genetic evidence underpins the overall pathogenic role of GTPBP2 in Jaberi-Elahi syndrome.
Molecular assessments reveal that the c.1289T>C (p.Leu430Pro) variant likely impairs the normal function of the GTPBP2 protein. Investigations have detailed the mutation’s impact at the protein level, with in vitro studies demonstrating aberrant protein behavior that may translate to the clinical phenotype. Functional studies in cellular systems have noted that mutant GTPBP2 can exhibit loss-of-function effects and altered subcellular localization, key indicators of pathogenicity (PMID:39971978). The experimental work supports a mechanism of haploinsufficiency or dominant‐negative impact resulting from the missense variant. While some experimental models have also been applied to related disorders, the convergence of molecular findings reinforces the causative role of the c.1289T>C (p.Leu430Pro) mutation. This detailed molecular characterization complements the clinical findings and solidifies the overall genetic narrative.
Functional evidence further bolsters the link between GTPBP2 defects and the neurodevelopmental aspects of Jaberi-Elahi syndrome. Studies employing cellular assays have demonstrated that altered protein dynamics, including abnormal cytoplasmic aggregation, are associated with loss-of-function outcomes (PMID:39971978). Additional assessments in model organisms have provided insights into the conserved role of GTPBP2 in central nervous system development, aligning with the observed motor delays and intellectual disabilities in patients (PMID:38118446). Although these functional studies were derived from related but distinct phenotypes, they contribute meaningful supportive evidence for a disruptive biological mechanism. The confluence of genetic and experimental data indicates a tangible impact on protein function that is relevant to the disease. This functional concordance is critical for the integration of translational insights into the diagnostic process.
In summary, the combined genetic and functional data provide a coherent and compelling narrative linking the c.1289T>C (p.Leu430Pro) variant in GTPBP2 to the pathogenesis of Jaberi-Elahi syndrome. The strong clinical validity, as captured by multiple independent reports and functional studies, supports the diagnostic utility of genetic testing in suspected cases. Although additional experimental evidence exists and exceeds the maximum ClinGen scoring cap, it further corroborates the pathogenetic mechanism. Key take‑home sentence: The robust evidence linking GTPBP2 loss-of-function to Jaberi-Elahi syndrome supports its clinical utility in diagnostic and therapeutic decision‑making.
Gene–Disease AssociationStrong27 individuals with Jaberi-Elahi syndrome reported (PMID:38852771); multiple studies demonstrate consistent clinical features and segregation. Genetic EvidenceStrongA homozygous missense variant c.1289T>C (p.Leu430Pro) identified in a patient, supported by multiple independent case series and literature review (PMID:38852771). Functional EvidenceModerateCellular and in vivo models demonstrate loss-of-function and aberrant protein aggregation consistent with the disease mechanism (PMID:39971978; PMID:38118446). |