Ambrose Anastasia, Caluseriu Oana, Mercimek-Andrews Saadet
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
Hum Mutat. 2025 Jun 12;2025:6490124. doi: 10.1155/humu/6490124. eCollection 2025.
Biallelic pathogenic variants in result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of variants in this study. We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and . We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date. We report three new individuals with Alazami syndrome and two novel variants in . We report the first missense variant associated with Alazami syndrome. We report the protein 3D structure of variants. We show a relationship between the p.Asp54Val variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.
双等位基因致病性变异会导致阿拉扎米综合征，其特征为全面发育迟缓、认知功能障碍和畸形特征。约30%的个体有心脏和骨骼表型。在本研究中，我们报告了三名患有阿拉扎米综合征的新个体以及该基因变异的功能特征。我们查阅了电子病历。我们应用了美国医学遗传学与基因组学学会以及分子病理学协会的变异分类算法。我们使用定量聚合酶链反应基因表达实验，通过3D蛋白质建模工具对该基因变异进行计算机预测和功能特征分析。我们查阅了关于阿拉扎米综合征和该基因的医学文献。我们报告了来自两个无亲缘关系家庭的三名个体，他们具有提示阿拉扎米综合征的特征性表型。通过临床外显子组测序，我们在家族1中鉴定出一个纯合的新型错义可能致病性变异（p.Asp54Val），在家族2中鉴定出一个纯合的新型致病性变异（p.Lys219Glu∗）。与野生型相比，3D蛋白质建模显示这两个变异都有较大的结构变化。功能特征分析显示，受影响个体与野生型对照之间LARP7表达存在统计学上的显著差异。我们报告了同一家庭内的表型变异性，心脏表型仅出现在家族1的病例2中。迄今为止，报告的阿拉扎米综合征患者不足60例。我们报告了三名患有阿拉扎米综合征的新个体以及该基因的两个新变异。我们报告了首个与阿拉扎米综合征相关的错义变异。我们报告了该基因变异的蛋白质3D结构。根据3D蛋白质建模预测工具，我们显示了p.Asp54Val变异与LARP7表达水平之间的关系。我们认为这可能是由于LARP7的RNA结合异常所致。
