RESUMO
SLC6A1 is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a 2-yr-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patient's variant ranks with other pathogenic variants. Genomic studies within the patient revealed a G443D variant of uncertain significance. Structural and evolutionary assessments establish this variant as a loss of function to the protein. Compiled metrics through our custom tools on sequence, structure, and protein dynamics combined with PolyPhen-2, PROVEAN, SIFT, and Align-GVGD reveal this variant to rank in the top functional outcome changes relative to gnomAD, TOPMed, and ClinVar variants known to date. The patient was resistant to multiple epileptic drugs, finally finding that valproic acid controls the seizures. This is consistent with additional groups studying SLC6A1 variants within patients.
Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Pré-Escolar , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Predisposição Genética para Doença/genética , Humanos , Deficiência Intelectual/genética , Mutação com Perda de Função/genética , Mutação/genética , Fenótipo , Convulsões/genética , Ácido Valproico/farmacologiaRESUMO
The immature stages are described for the first time for Chironomus (Xenochironomus) australiensis Freeman (Diptera: Chironomidae) and the adult male is redescribed including from type specimens. The species does not belong to Chironomus Meigen or Xenochironomus Kieffer, but is best placed in a modestly expanded Einfeldia Kieffer. Application of this genus name is clarified, including by a lectotype fixation for its type species, E. pectoralis Kieffer, 1924. Einfeldia australiensis (Freeman) comb. n. provides the first record of the genus from Australia; otherwise the genus is reported confidently only from North America, Central America and western Europe to Japan. The immature stages of E. australiensis occur in relatively shallow mesotrophic to eutrophic dune lakes and maars with circum-neutral pH and high conductivity, from southeastern Queensland to southern Australia. The cytology is described briefly from larval salivary glands. Alternative genus placements for the species are discussed, and problems with Einfeldia and connected systematics in the tribe Chironomini are addressed.