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Abstract：
Purpose: Alström syndrome (AS) is a rare autosomal recessive disorder caused by variants of ALMS1. The objectives of this study were to describe the clinical and genetic characteristics of 19 Chinese patients with biallelic variants in ALMS1. Methods: We recruited 19 probands with biallelic disease-causing ALMS1 variants. All patients underwent ophthalmic and systematic evaluations and comprehensive molecular genetic analysis. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays were performed to observe the effect of a novel missense variant on ALMS1 pre-mRNA splicing. Results: We identified 33 causative variants in ALMS1, including 15 frameshift small indels, 14 non-sense variants, two gross deletions, one splicing variant, and one missense variant. RT-PCR showed that the missense variant c.9542G>A (p.R3181Q) altered pre-mRNA splicing to generate a truncated protein p. (Ser3082Asnfs*6). Retinal dystrophy (RD) was noted in all the patients, followed by metabolism disturbance (obesity or acanthosis nigricans) in 66.7% and hearing impairment in 61.1% of the patients. Patient systemic symptom numbers and their age at evaluation showed a significant positive correlation, and BCVA and age at the last examination showed a moderate correlation. All patients exhibited early-onset RD and severe visual impairment. The exception was one patient carrying homozygous p. R3181Q, who showed a mild visual defect and atypical retinal phenotype. Conclusion: Our findings expand the pathogenic variant spectrum of ALMS1 and provide the first verification of a novel missense variant caused AS by aberrant pre-mRNA splicing. Patients with AS might demonstrate varied clinical spectra; therefore, genetic analysis is vital for the early and accurate diagnosis of patients with atypical AS.
摘要：
目的：Alström综合征（AS）是由ALMS1变异引起的一种罕见的常染色体隐性遗传疾病。这项研究的目的是描述19名中国人在ALMS1中具有双等位基因变异的患者的临床和遗传特征。方法：我们招募了19名双等位基因致病ALMS1变异的先证者。所有患者均接受眼科和系统评估以及全面的分子遗传学分析。进行逆转录酶聚合酶链反应（RT-PCR）测定以观察新型错义变体对ALMS1前mRNA剪接的影响。结果：我们确定了ALMS1中的33个致病变异，包括15个移码小插入缺失，14个无义变体，两个总删除，一个剪接变体，和一个错觉变体。RT-PCR显示错义变体c.9542G>A（p。R3181Q）改变前mRNA剪接以产生截短的蛋白质p。（Ser3082Asnfs*6）。所有患者均注意到视网膜营养不良（RD），其次是66.7%的患者的代谢紊乱(肥胖或黑棘皮病)和61.1%的患者的听力障碍。患者的全身症状数量和他们在评估时的年龄显示出显着的正相关，在最后一次检查时，BCVA和年龄呈中等相关性。所有患者均表现为早发性RD和严重的视力障碍。例外是一名患者携带纯合p。R3181Q，显示轻度视觉缺陷和非典型视网膜表型。结论：我们的发现扩展了ALMS1的致病变异谱，并首次验证了由异常pre-mRNA剪接引起的AS的新型错义变异。AS患者可能表现出不同的临床谱；因此，基因分析对于非典型AS患者的早期和准确诊断至关重要。
