PDF(Pubmed)
Abstract：
UNASSIGNED: CHARGE syndrome is a congenital hereditary condition involving multiple systems. Patients are easily misdiagnosed with idiopathic hypogonadotropic hypogonadism (IHH) due to the overlap of clinical manifestations. An accurate clinical diagnosis remains challenging when the predominant clinical manifestation resembles hypogonadotropic hypogonadism.
UNASSIGNED: This original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants.
UNASSIGNED: WES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability.
UNASSIGNED: We identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.
UNASSIGNED: This original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants.
UNASSIGNED: WES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability.
UNASSIGNED: We identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.
摘要：
■CHARGE综合征是一种涉及多个系统的先天性遗传性疾病。由于临床表现的重叠，患者容易被误诊为特发性低促性腺激素性性腺功能减退症（IHH）。当主要的临床表现类似于低促性腺激素性腺功能减退症时，准确的临床诊断仍然具有挑战性。
■这项原始研究是根据对临床病例的遗传发现和分析进行的。对两个姐妹进行了全外显子组测序（WES）和计算机分析，以研究该家族的发病机理。进行同源性建模以评估变体中的结构变化。
■WES和Sanger测序显示，两个兄弟姐妹在CHD7的第2外显子中携带一个无义突变（NM_017780.4：c.115C>T），该突变是从轻度受影响的母亲继承的，并且在SMCHD1的第20外显子中存在一个错义突变（NM_015295.3：c.2582T>C）。预测CHD7中的无义突变会产生无义介导的衰变，而SMCHD1中的错义突变降低了蛋白质的稳定性。
■我们首次在IHH相关疾病中鉴定了双基因CHD7和SMCHD1突变，并验证了寡基因遗传的协同作用。还确定WES是区分具有重叠特征的疾病并为具有双基因或低基因遗传性疾病的病例建立分子诊断的有效工具。这有利于及时治疗，和家庭遗传咨询。
■这项原始研究是根据对临床病例的遗传发现和分析进行的。对两个姐妹进行了全外显子组测序（WES）和计算机分析，以研究该家族的发病机理。进行同源性建模以评估变体中的结构变化。
■WES和Sanger测序显示，两个兄弟姐妹在CHD7的第2外显子中携带一个无义突变（NM_017780.4：c.115C>T），该突变是从轻度受影响的母亲继承的，并且在SMCHD1的第20外显子中存在一个错义突变（NM_015295.3：c.2582T>C）。预测CHD7中的无义突变会产生无义介导的衰变，而SMCHD1中的错义突变降低了蛋白质的稳定性。
■我们首次在IHH相关疾病中鉴定了双基因CHD7和SMCHD1突变，并验证了寡基因遗传的协同作用。还确定WES是区分具有重叠特征的疾病并为具有双基因或低基因遗传性疾病的病例建立分子诊断的有效工具。这有利于及时治疗，和家庭遗传咨询。
