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Recent evidence supports an association between KBTBD13 and congenital myopathy. Multiple independent studies—including case report reviews and large multi‑patient exome sequencing projects—have implicated KBTBD13 in the spectrum of congenital myopathies, with clinical features ranging from early childhood weakness to adult-onset disease (PMID:27538056, PMID:38982518).
Genetic investigations indicate an autosomal dominant mode of inheritance. Detailed segregation analyses in affected families have identified additional affected relatives carrying KBTBD13 variants, further supporting the causative role of this gene. Although the exact number of probands is not always specified, the cumulative evidence from multiple unrelated families underscores the relevance of KBTBD13 abnormalities in congenital myopathy (PMID:27538056).
A representative pathogenic variant reported in KBTBD13 is c.1222C>T (p.Arg408Cys). This variant, following strict HGVS nomenclature with three‑letter amino acid codes, has been observed in association with muscle weakness and other myopathic features. Its identification in patients supports its utility in molecular diagnosis and highlights the importance of genetic testing in ambiguous clinical cases.
Functional studies lend further credence to the role of KBTBD13 in disease pathogenesis. Experimental evidence from ubiquitination assays and protein–protein interaction studies has demonstrated that KBTBD13 interacts with Cullin‑3, forming a functional RING ubiquitin ligase complex. This mechanistic insight is consistent with the muscle pathology observed in congenital myopathy patients and suggests that dysregulation of protein turnover contributes to disease development (PMID:22542517, PMID:30990797).
Importantly, while KBTBD13 has also been implicated in related myopathic conditions such as nemaline myopathy and cardiomyopathy, the evidence for its role in congenital myopathy is supported by both clinical and experimental data. The convergence of segregation information, identification of a recurrent variant, and supportive functional assays provides a coherent framework for its pathogenic involvement.
Overall, the integration of genetic and experimental findings indicates a moderate level of clinical validity for the KBTBD13–congenital myopathy association. Although additional studies may further augment the evidence beyond current ClinGen scoring limits, the data available already hold clear clinical utility by aiding diagnostic decision‑making and patient management.
Key take‑home sentence: The association between KBTBD13 and congenital myopathy is supported by multiple lines of genetic and functional evidence, underscoring its value in refining diagnosis and guiding clinical care.
Gene–Disease AssociationModerateEvidence from multiple independent case reports and a large multi‑patient study demonstrates segregation of KBTBD13 variants with congenital myopathy phenotypes (PMID:27538056, PMID:38982518). Genetic EvidenceModerateAutosomal dominant inheritance with recurrent identification of variants (e.g., c.1222C>T leading to p.Arg408Cys) and segregation across affected relatives supports a pathogenic link for congenital myopathy. Functional EvidenceModerateFunctional assays demonstrating KBTBD13’s interaction with Cul3 and its role in ubiquitin ligase activity provide mechanistic support for its involvement in muscle pathology, aligning with the congenital myopathy phenotype (PMID:22542517, PMID:30990797). |