MODY probability calculator for GCK and HNF1A screening in a multiethnic background population

ABSTRACT Objective We aimed to identify the frequency of monogenic diabetes, which is poorly studied in multiethnic populations, due to GCK or HNF1A mutations in patients with suggestive clinical characteristics from the Brazilian population, as well as investigate if the MODY probability calculator (MPC) could help patients with their selection. Subjects and methods Inclusion criteria were patients with DM diagnosed before 35 years; body mass index < 30 kg/m2; negative autoantibodies; and family history of DM in two or more generations. We sequenced HNF1A in 27 patients and GCK in seven subjects with asymptomatic mild fasting hyperglycemia. In addition, we calculated MODY probability with MPC. Results We identified 11 mutations in 34 patients (32.3%). We found three novel mutations. In the GCK group, six cases had mutations (85.7%), and their MODY probability on MPC was higher than 50%. In the HNF1A group, five of 27 individuals had mutations (18.5%). The MPC was higher than 75% in 11 subjects (including all five cases with HNF1A mutations). Conclusion Approximately one third of the studied patients have GCK or HNF1A mutations. Inclusion criteria included efficiency in detecting patients with GCK mutations but not for HNF1A mutations (< 20%). MPC was helpful in narrowing the number of candidates for HNF1A screening.

摘要
研究目的：旨在明确巴西多族裔人群中具有疑似临床特征的糖尿病患者因GCK或HNF1A突变导致的单基因糖尿病（monogenic diabetes）患病率——该人群的相关研究目前仍较为匮乏——同时探讨青少年起病的成人型糖尿病（MODY, Maturity-Onset Diabetes of the Young）概率计算器（MPC, MODY Probability Calculator）能否辅助此类患者的筛选。
研究对象与方法：纳入标准为35岁前确诊糖尿病（DM, Diabetes Mellitus）、体重指数（BMI, Body Mass Index）<30 kg/m²、自身抗体检测阴性，且存在两代及以上糖尿病家族史的患者。本研究对27例患者开展HNF1A基因测序，对7例无症状轻度空腹高血糖受试者开展GCK基因测序；同时通过MPC计算MODY发病概率。
研究结果：共在34例患者中检出11处突变，检出率为32.3%，其中包含3处全新突变。在GCK基因测序组中，6例检出突变，检出率达85.7%，且该组患者的MPC MODY概率评分均高于50%。在HNF1A基因测序组中，27例患者中有5例检出突变，检出率为18.5%。共有11例受试者的MPC MODY概率评分高于75%，其中涵盖全部5例HNF1A突变阳性患者。
研究结论：本次纳入研究的患者中，约三分之一存在GCK或HNF1A基因突变。本研究采用的纳入标准可有效筛选出GCK突变阳性患者，但对HNF1A突变阳性患者的筛选效率不足20%。MPC可有效缩小HNF1A基因筛查的候选人群范围。