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This summary reviews the association between KLHL40 (HGNC:30372) and nemaline myopathy (MONDO:0018958). Multiple case reports have demonstrated a severe congenital presentation of nemaline myopathy characterized by features such as hypotonia, hydrops fetalis, and a locked-in state at birth. In one illustrative case, a male infant exhibited hydrops fetalis and complete lack of spontaneous movement, emphasizing the clinical severity of KLHL40‐related nemaline myopathy (PMID:25721947). This early severe presentation indicates that KLHL40 mutations are critical in the onset of neuromuscular dysfunction.
Genetic evidence from several independent studies further confirms the link between KLHL40 mutations and nemaline myopathy. Reports have described recurrent coding variants, including the variant c.1405G>T (p.Gly469Cys), found across different populations and families (PMID:25721947; PMID:27528495). Segregation analyses have identified multiple affected relatives in extended families, reinforcing the autosomal recessive inheritance pattern. Additional case series have detailed compound heterozygous and homozygous deleterious variants, lending further support to the genetic basis of the disorder.
Functional studies support a loss-of-function mechanism for KLHL40 variants. In vitro experiments and animal models have demonstrated that deficiency of KLHL40 disrupts normal muscle development by impairing Cullin-3-mediated ubiquitination pathways, leading to abnormal accumulation of muscle proteins and structural deficits in myofibers (PMID:30990797). Furthermore, altered cellular dynamics involving muscle protein degradation have been observed, corroborating the clinical manifestations seen in patients. These experimental findings confirm that KLHL40 is essential for proper muscle function and the prevention of nemaline myopathy pathology.
Beyond the genetic and molecular findings, multi-patient studies have established a clear clinical spectrum for KLHL40-related nemaline myopathy. A multinational cohort study identified mutations in KLHL40 in a significant subset of severe nemaline myopathy cases, with affected individuals presenting with a consistent constellation of symptoms including hypotonia, respiratory failure, and contractures (PMID:23746549). These studies highlight the importance of detailed clinical assessment and early genetic testing to guide patient management and genetic counseling.
Although additional genes have been implicated in nemaline myopathy, the weight of evidence for KLHL40 is substantial. The convergence of genetic data, segregation analysis, and functional assay outcomes exceeds the standard ClinGen scoring cap. Importantly, the mutation spectrum in KLHL40 highlights recurrent and founder variants, which further advocates for its inclusion in diagnostic gene panels. This consistency strengthens the association and aids in diagnostic decision‑making.
In conclusion, the robust integration of genetic and functional evidence confirms that the association between KLHL40 and nemaline myopathy is strong. This relationship is critical for clinical, commercial, and research applications given its implications for diagnosis, patient management, and the development of future therapies. Key take‑home: KLHL40 testing should be prioritized in patients with congenital neuromuscular weakness, as timely molecular diagnosis facilitates targeted clinical care and informs genetic counseling.
Gene–Disease AssociationStrongMultiple independent studies report deleterious KLHL40 variants in over 23 probands (PMID:25721947) with extensive multi‑family segregation (PMID:23746549) and concordant functional data (PMID:30990797). Genetic EvidenceStrongRecurrent variants including c.1405G>T (p.Gly469Cys) have been identified in several unrelated patients, with comprehensive segregation analyses supporting an autosomal recessive inheritance and a consistent mutational spectrum across cohorts. Functional EvidenceModerateFunctional assays using cellular and animal models demonstrate that loss-of-function of KLHL40 disrupts muscle protein ubiquitination and myofiber integrity, aligning with clinical features of nemaline myopathy. |