PDF(Pubmed)
Abstract：
UNASSIGNED: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project.
UNASSIGNED: We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in ACTG2, ACTA2, MYH11, MYLK, LMOD1, CHRM3, MYL9, FLNA and KNCMA1 by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort.
UNASSIGNED: We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in KCNMA1 which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 variants as the largest contributor to VM-related phenotypes.
UNASSIGNED: VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified ACTG2 as the most frequent genetic cause of VM. We recommend a nomenclature change to \'autosomal dominant ACTG2 visceral myopathy\' for patients with pathogenic variants in ACTG2 and associated VM phenotypes.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s44162-023-00012-z.
UNASSIGNED: We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in ACTG2, ACTA2, MYH11, MYLK, LMOD1, CHRM3, MYL9, FLNA and KNCMA1 by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort.
UNASSIGNED: We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in KCNMA1 which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 variants as the largest contributor to VM-related phenotypes.
UNASSIGNED: VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified ACTG2 as the most frequent genetic cause of VM. We recommend a nomenclature change to \'autosomal dominant ACTG2 visceral myopathy\' for patients with pathogenic variants in ACTG2 and associated VM phenotypes.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s44162-023-00012-z.
摘要：
内脏肌病(VM)是一组以收缩性或收缩性平滑肌差为特征的疾病。它们在GI和GU区域都有表现，从巨大的乳房到修剪腹部综合症。我们旨在应用定制的虚拟遗传面板，并使用基因组英格兰100,000基因组项目中的全基因组测序数据描述与这种情况相关的新变异。
■我们筛选了基因组英格兰100,000基因组计划罕见疾病数据库中的VM相关表型患者。这些患者在ACTG2、ACTA2、MYH11、MYLK、LMOD1，CHRM3，MYL9，FLNA和KNCMA1通过分析全基因组测序数据。使用变异效应预测在线工具分析识别出的变异，其他家族成员中任何可能的分离和新的错义突变都是使用计算机模拟工具进行建模的。VM队列还用于进行全基因组变异负荷测试，以鉴定该队列中的基因关联。
■我们确定了76例表型与VM诊断一致的患者。介绍的范围包括巨结肠/微结肠蠕动综合征，李子腹综合征与慢性假性肠梗阻。在我们鉴定杂合ACTG2变异体的患者中，7个有可能的致病变异，包括1个新的可能的致病等位基因。有4名患者，我们鉴定出具有不确定意义的杂合MYH11变体，该变体导致移码和预测的蛋白质伸长。我们确定了一个家族，在该家族中我们发现了KCNMA1中具有不确定意义的杂合变体，该变体在计算机模型中预测是致病的，并且可以解释所看到的VM表型。我们没有在导致VM相关疾病表型的已知基因中发现任何CNV变化。在这个表型选择的队列中，ACTG2是VM相关疾病的最大单基因原因，占队列的9％，由变体负担测试方法支持，该研究确定ACTG2变体是VM相关表型的最大贡献者。
■VM是一组不易分类的疾病，可以根据其表型给予不同的诊断标记。这些患者的分子遗传学分析是有价值的，因为它可以精确诊断并有助于了解潜在的疾病表现。我们确定ACTG2是VM最常见的遗传原因。对于ACTG2致病变异和相关VM表型的患者，我们建议对“常染色体显性遗传ACTG2内脏肌病”进行命名改变。
■在线版本包含10.1007/s44162-023-00012-z提供的补充材料。
■我们筛选了基因组英格兰100,000基因组计划罕见疾病数据库中的VM相关表型患者。这些患者在ACTG2、ACTA2、MYH11、MYLK、LMOD1，CHRM3，MYL9，FLNA和KNCMA1通过分析全基因组测序数据。使用变异效应预测在线工具分析识别出的变异，其他家族成员中任何可能的分离和新的错义突变都是使用计算机模拟工具进行建模的。VM队列还用于进行全基因组变异负荷测试，以鉴定该队列中的基因关联。
■我们确定了76例表型与VM诊断一致的患者。介绍的范围包括巨结肠/微结肠蠕动综合征，李子腹综合征与慢性假性肠梗阻。在我们鉴定杂合ACTG2变异体的患者中，7个有可能的致病变异，包括1个新的可能的致病等位基因。有4名患者，我们鉴定出具有不确定意义的杂合MYH11变体，该变体导致移码和预测的蛋白质伸长。我们确定了一个家族，在该家族中我们发现了KCNMA1中具有不确定意义的杂合变体，该变体在计算机模型中预测是致病的，并且可以解释所看到的VM表型。我们没有在导致VM相关疾病表型的已知基因中发现任何CNV变化。在这个表型选择的队列中，ACTG2是VM相关疾病的最大单基因原因，占队列的9％，由变体负担测试方法支持，该研究确定ACTG2变体是VM相关表型的最大贡献者。
■VM是一组不易分类的疾病，可以根据其表型给予不同的诊断标记。这些患者的分子遗传学分析是有价值的，因为它可以精确诊断并有助于了解潜在的疾病表现。我们确定ACTG2是VM最常见的遗传原因。对于ACTG2致病变异和相关VM表型的患者，我们建议对“常染色体显性遗传ACTG2内脏肌病”进行命名改变。
■在线版本包含10.1007/s44162-023-00012-z提供的补充材料。
