Abstract：
OBJECTIVE: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD).
METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants.
RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR.
CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.
METHODS: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants.
RESULTS: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR.
CONCLUSIONS: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.
摘要：
目的：Alström综合征（AS）是一种罕见的以糖尿病为特征的隐性疾病，肥胖，胰岛素抵抗（IR），视觉和听觉障碍。ALMS1基因中的突变已被鉴定为AS的致病因子。本研究旨在探讨中国早发性2型糖尿病患者（诊断年龄≤40岁；EOD）的罕见ALMS1变异与临床特征之间的关系。
方法：对611名中国EOD患者进行ALMS1基因测序，36与餐后高胰岛素血症，和47患有糖尿病前期和空腹IR。使用计算机预测算法和美国医学遗传学学会指南（ACMG）来评估变体的有害性和致病性。
结果：在82例EOD患者中发现了62种罕见的ALMS1变异（频率<0.005）。预测19种变体是有害的(pD)。携带pD变异的EOD患者有较高的空腹C肽，餐后C肽，和HOMA2-IR水平比那些没有变体。具有更多胰岛素抵抗EOD的亚组中ALMS1pD变体的频率高于其他EOD亚组。两名EOD患者,肥胖，根据ACMG鉴定了携带ALMS1杂合致病性/可能致病性罕见变体的IR。此外，在餐后高胰岛素血症以及空腹IR的糖尿病前期队列的参与者中发现了ALMS1的罕见杂合pD变体。
结论：ALMS1稀有pD变体在具有显著IR的群体中富集，这是糖尿病发病机制的主要标志。因此，我们的探索性研究为进一步研究基因功能提供了见解和假设。
方法：对611名中国EOD患者进行ALMS1基因测序，36与餐后高胰岛素血症，和47患有糖尿病前期和空腹IR。使用计算机预测算法和美国医学遗传学学会指南（ACMG）来评估变体的有害性和致病性。
结果：在82例EOD患者中发现了62种罕见的ALMS1变异（频率<0.005）。预测19种变体是有害的(pD)。携带pD变异的EOD患者有较高的空腹C肽，餐后C肽，和HOMA2-IR水平比那些没有变体。具有更多胰岛素抵抗EOD的亚组中ALMS1pD变体的频率高于其他EOD亚组。两名EOD患者,肥胖，根据ACMG鉴定了携带ALMS1杂合致病性/可能致病性罕见变体的IR。此外，在餐后高胰岛素血症以及空腹IR的糖尿病前期队列的参与者中发现了ALMS1的罕见杂合pD变体。
结论：ALMS1稀有pD变体在具有显著IR的群体中富集，这是糖尿病发病机制的主要标志。因此，我们的探索性研究为进一步研究基因功能提供了见解和假设。
