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Abstract：
Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype-phenotype relationships.
Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.
DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.
The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.
Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.
DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.
The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.
摘要：
染色体柔性铰链域含蛋白1（SMCHD1）的结构维持变异可导致面肩肱肌营养不良2型（FSHD2）和无关的Bosmaarhinia小眼综合征（BAMS）。在FSHD2中，在SMCHD1中的任何地方都发现了致病变体，而在BAMS中，致病变体仅限于延伸的ATPase结构域.无论表型结果如何，FSHD2相关和BAMS相关的SMCHD1变体均导致可量化的局部DNA低甲基化.我们比较了FSHD2，BAMS和非致病性SMCHD1变体，以得出基因型-表型关系。
检查187个FSHD2家族中SMCHD1敏感的FSHD基因座DUX4的SMCHD1变体和甲基化，41例BAMS患者和对照个体。SMCHD1的ATPase结构域的三维模型中的变体分析。
DUX4甲基化分析对于建立SMCHD1变体的致病性至关重要。尽管FSHD2突变谱包括覆盖整个SMCHD1基因座的所有类型的变体,错义变体在延伸的ATP酶结构域中显著富集。复发性变异的鉴定表明FSHD2和BAMS中的疾病特异性残留，与SMCHD1中变异体的疾病特异性定位一致。
SMCHD1的ATPase结构域内错义变体的定位可能导致表型结果的差异。
检查187个FSHD2家族中SMCHD1敏感的FSHD基因座DUX4的SMCHD1变体和甲基化，41例BAMS患者和对照个体。SMCHD1的ATPase结构域的三维模型中的变体分析。
DUX4甲基化分析对于建立SMCHD1变体的致病性至关重要。尽管FSHD2突变谱包括覆盖整个SMCHD1基因座的所有类型的变体,错义变体在延伸的ATP酶结构域中显著富集。复发性变异的鉴定表明FSHD2和BAMS中的疾病特异性残留，与SMCHD1中变异体的疾病特异性定位一致。
SMCHD1的ATPase结构域内错义变体的定位可能导致表型结果的差异。
