RESUMO
BACKGROUND: Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide. METHODS: We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations. RESULTS: We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10-7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype-phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14-23% of MH families. CONCLUSIONS: Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
Assuntos
Hipertermia Maligna/epidemiologia , Hipertermia Maligna/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Canais de Cálcio/genética , Canais de Cálcio Tipo L , Estudos de Coortes , Simulação por Computador , Exoma , Família , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Reino Unido/epidemiologiaAssuntos
Idoso , Terapia Ocupacional , Idoso de 80 Anos ou mais , Exercício Físico , Promoção da Saúde , HumanosRESUMO
Orders for removal under Section 47 of the 1948 National Assistance Act are little discussed. However, they involve severe infringements of the civil liberties of those affected. It is argued that all previously presented justifications for the use of these orders fail. Repeal of the act is called for. The Law Commission has drafted alternative legislation, but this has not been enacted. Until this occurs local authorities, the Faculty of Public Health Medicine and individual public health physicians should refuse to be involved in its use.
