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Autosomal recessive progressive myoclonus epilepsy (PME) is characterized by myoclonic seizures, ataxia, and rapid neurocognitive decline. Biallelic pathogenic variants in KCTD7 have been identified in a total of 18 unrelated patients from nine families, including both consanguineous and outbred pedigrees ([PMID:22693283]). Reported variants encompass missense, nonsense, frameshift, splice-site, in-frame deletion, and large multi-exon deletions, with a recurrent truncating change c.295C>T (p.Arg99Ter) detected in multiple families ([PMID:22693283]). Compound heterozygous presentations, such as c.250C>T (p.Arg84Trp) together with an exon 3–4 deletion, expand the phenotypic spectrum to include opsoclonus-myoclonus ataxia and steroid-responsive features ([PMID:22638565]).
Segregation analysis across these families confirms autosomal recessive inheritance: unaffected parents carry heterozygous KCTD7 variants and affected siblings are compound heterozygous or homozygous for deleterious alleles, with co-segregation in all available relatives. No phenotypic manifestations are observed in carriers, supporting complete penetrance in the biallelic state.
Functional studies demonstrate that wild-type KCTD7 promotes neuronal membrane hyperpolarization and regulates K+-dependent glutamine transport via SAT2, whereas truncating and missense variants (e.g., p.Phe232LeufsTer?, p.Arg94Gln, p.Tyr276Cys, p.Arg184Cys) abolish these effects in Xenopus oocyte assays ([PMID:27742667]). Patch-clamp recordings in transfected neurons corroborate a loss of K+ conductance for patient alleles ([PMID:21710140]). Moreover, kctd7 knockout zebrafish recapitulate motor deficits and neurodegeneration, reinforcing a conserved role in neuronal excitability ([PMID:33970744]).
Additional work in patient fibroblasts and yeast models uncovers impaired autophagy-lysosomal clearance and accumulation of lipofuscin-like deposits, linking KCTD7 deficiency to a conserved autophagy-lysosome defect rather than classical NCL pathology ([PMID:30295347]). These mechanistic insights integrate ion channel dysregulation with autophagic failure in KCTD7-associated PME.
Although population databases contain rare KCTD7 variants of uncertain significance, comprehensive genetic and biochemical assays—including disrupted Cullin-3 interactions and altered ubiquitination profiles—support the deleterious impact of patient-derived alleles and refute benign polymorphism assignments ([PMID:30295347]).
Collectively, the evidence fulfills ClinGen criteria for a definitive gene–disease relationship: robust segregation in multiple families, replication across independent cohorts, and concordant functional and animal model data. KCTD7 genetic testing is clinically indicated for early-onset PME with myoclonus and ataxia, informing diagnosis, genetic counseling, and potential targeted therapies.
Gene–Disease AssociationDefinitive18 probands in nine unrelated families with consistent biallelic segregation and extensive concordant functional and animal model data Genetic EvidenceStrongMultiple biallelic variant types (missense, truncating, splice, copy-number) identified in 18 patients from nine families with autosomal recessive inheritance Functional EvidenceStrongXenopus oocyte and neuronal patch-clamp assays, zebrafish knockout, and autophagy-lysosome studies all demonstrate loss of KCTD7 function |