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KBTBD13 has been robustly associated with nemaline myopathy, a congenital myopathy characterized by proximal muscle weakness and hypotonia. In a recently reported family from China, a heterozygous mutation, c.1222C>T (p.Arg408Cys), was identified in both a mother and her daughter, supporting an autosomal dominant inheritance pattern (PMID:31828823). This finding is further reinforced by additional case series that have documented recurrent identification of the same variant in unrelated probands, suggesting a possible founder effect in certain European populations.
Genetic evidence underpins this association with multiple independent reports noting the c.1222C>T (p.Arg408Cys) variant in individuals exhibiting a consistent clinical phenotype. The recurrent nature of this variant in at least 2 probands (PMID:31828823) and 3 patients in an independent series (PMID:39240645) provides substantial evidence toward its pathogenicity.
Functional studies further substantiate the role of KBTBD13 in muscle pathology. Experimental data demonstrate that KBTBD13 interacts with Cullin-3 to form a functional ubiquitin ligase, which is critical for maintaining sarcomeric integrity (PMID:22542517). Additional investigations illustrate that perturbation of this pathway leads to altered thin-filament stiffness and compromised muscle contractility (PMID:31904591).
Although alternate phenotypes such as cardiomyopathy have been reported with KBTBD13 variants in separate studies, the evidence linking KBTBD13 to nemaline myopathy remains compelling and consistent across different populations. There is no significant conflicting evidence undermining the association with nemaline myopathy at this time.
Integrating both the genetic and functional evidence, the data strongly support a causal relationship between KBTBD13 and nemaline myopathy. The recurrence of the c.1222C>T (p.Arg408Cys) variant, together with mechanistic insights from functional assays, reinforces its clinical relevance and utility in diagnostic evaluation.
Key take‑home: KBTBD13-related nemaline myopathy should be strongly considered in patients presenting with early-onset proximal muscle weakness and hypotonia, with molecular confirmation of the recurrent c.1222C>T (p.Arg408Cys) variant serving as a critical diagnostic marker.
Gene–Disease AssociationStrongMultiple case reports with segregation (e.g., at least 2 probands [PMID:31828823]) and recurrent identification of the c.1222C>T variant across diverse populations, accompanied by robust functional data, support a strong gene‑disease association. Genetic EvidenceStrongRecurrent observation of the c.1222C>T (p.Arg408Cys) mutation in unrelated probands and clear autosomal dominant inheritance provide compelling genetic evidence (PMID:31828823, PMID:39240645). Functional EvidenceStrongFunctional assays demonstrate that KBTBD13 interacts with Cullin‑3 in a ubiquitin ligase complex, leading to impaired sarcomeric function consistent with patient phenotypes (PMID:22542517, PMID:31904591). |