RESUMO
KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.
Assuntos
Transtornos dos Movimentos/genética , Transtornos do Neurodesenvolvimento/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Adolescente , Adulto , Ataxia Cerebelar/genética , Ataxia Cerebelar/psicologia , Criança , Pré-Escolar , Fenômenos Eletrofisiológicos , Exoma , Mutação da Fase de Leitura , Variação Genética , Haploinsuficiência , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/psicologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/psicologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/psicologia , Técnicas de Patch-Clamp , Substância Branca/anormalidades , Substância Branca/diagnóstico por imagem , Adulto JovemRESUMO
Monogenic diabetes resulting from mutations that primarily reduce insulin-secreting pancreatic ß-cell function accounts for 1-2% of all cases of diabetes, and is genetically and clinically heterogeneous. Currently, genetic testing for monogenic diabetes relies on selection of the appropriate gene for analysis based on the availability of comprehensive phenotypic information, which can be time consuming, costly and can limit the differential diagnosis to a few selected genes. In recent years, the exponential growth in the field of high-throughput capture and sequencing technology has made it possible and cost effective to sequence many genes simultaneously, making it an efficient diagnostic tool for clinically and genetically heterogeneous disorders such as monogenic diabetes. Making a diagnosis of monogenic diabetes is important as it enables more appropriate treatment, better prediction of disease prognosis and progression, and counseling and screening of family members. We provide a concise overview of the genetic etiology of some forms of monogenic diabetes, as well as a discussion of the clinical utility of genetic testing by comprehensive multigene panel using next-generation sequencing methodologies.