PDF(Pubmed)
Abstract：
Defects in motile cilia, termed motile ciliopathies, result in clinical manifestations affecting the respiratory and reproductive system, as well as laterality defects and hydrocephalus. We previously defined biallelic MNS1 variants causing situs inversus and male infertility, mirroring the findings in Mns1-/- mice. Here, we present clinical and genomic findings in five newly identified individuals from four unrelated families affected by MNS1-related disorder. Ciliopathy panel testing and whole exome sequencing identified one previously reported and two novel MNS1 variants extending the genotypic spectrum of disease. A broad spectrum of laterality defects including situs inversus totalis and heterotaxia was confirmed. Interestingly, a single affected six-year-old girl homozygous for an MNS1 nonsense variant presented with a history of neonatal respiratory distress syndrome, recurrent respiratory tract infections, chronic rhinitis, and wet cough. Accordingly, immunofluorescence analysis showed the absence of MNS1 from the respiratory epithelial cells of this individual. Two other individuals with hypomorphic variants showed laterality defects and mild respiratory phenotype. This study represents the first observation of heterotaxia and respiratory disease in individuals with biallelic MNS1 variants, an important extension of the phenotype associated with MNS1-related motile ciliopathy disorder.
摘要：
活动纤毛的缺陷，称为能动纤毛病，导致影响呼吸系统和生殖系统的临床表现，以及侧向缺陷和脑积水。我们先前定义了双等位基因MNS1变异，导致坐位倒置和男性不育，反映了Mns1-/-小鼠的发现。这里,我们介绍了5个新发现的个体的临床和基因组发现,这些个体来自4个无关的受MNS1相关疾病影响的家庭.纤毛病组测试和全外显子组测序确定了一个先前报道的和两个新的MNS1变体，扩展了疾病的基因型谱。确认了广泛的侧向缺陷，包括全位倒置和异位性。有趣的是,一名患有MNS1无义变异的6岁女孩纯合子，有新生儿呼吸窘迫综合征病史，反复呼吸道感染，慢性鼻炎,还有湿咳.因此，免疫荧光分析显示该个体的呼吸道上皮细胞不存在MNS1。另外两个具有低态变异的个体显示出侧向缺陷和轻度呼吸表型。这项研究代表了在具有双等位基因MNS1变体的个体中异位性和呼吸系统疾病的首次观察。与MNS1相关的能动纤毛病相关的表型的重要扩展。
