目的:单基因糖尿病估计占主要非血缘人群儿科糖尿病病例的1-6%,而近亲地区的发病率和遗传谱定义不足。在这项单中心研究中,我们旨在评估糖尿病亚型,获得血缘率,并研究血缘率较高的人群中综合征型和新生儿糖尿病个体的遗传背景。
方法:数据收集于2021年11月在儿科糖尿病诊所进行,JamalAhmadRashed医院医生,在苏莱曼尼,库尔德斯坦,伊拉克。在收集数据的时候,登记了754名16岁以下的糖尿病患者(381名男孩)。相关参与者数据来自患者档案。735(97.5%)参与者已知血缘关系。此外,12个新生儿糖尿病儿童家庭和7个糖尿病综合征儿童家庭同意通过下一代测序进行基因检测。使用美国医学遗传学和基因组学学院指南评估优先考虑的变体,并通过Sanger测序进行确认。
结果:735名参与者中有269名(36.5%)具有已知的血亲状态是血亲家庭的后代。绝大多数参与者(714/754,94.7%)患有临床定义的1型糖尿病(其中35%是亲生父母)。而只有8人(1.1%)患有2型糖尿病(38%血缘性).14人(1.9%)患有新生儿糖尿病(50%血缘性),7例(0.9%)患有综合征型糖尿病(100%血缘性),11例(1.5%)患有临床定义的MODY(18%血缘性).我们发现血缘关系与综合征型糖尿病显著相关(p=0.0023),但与任何其他糖尿病亚型无关。在同意进行基因检测的12名新生儿糖尿病参与者中,有10名阐明了遗传原因(GLIS3[兄弟姐妹对]中的纯合变体,PTF1A和ZNF808以及ABCC8和INS中的杂合变体)和七名患有综合征性糖尿病的参与者中的四名(INSR中的纯合变体,SLC29A3和WFS1[兄弟对])。此外,一名被称为综合征型糖尿病的参与者被诊断为γ-粘脂症,可能患有2型糖尿病.
结论:这项独特的单中心研究证实,即使在高度近亲的人群中,临床定义的1型糖尿病是常见的儿科糖尿病亚型.此外,在83%的新生儿糖尿病受试参与者和57%的综合征型糖尿病参与者中确定了单基因糖尿病的致病原因,大多数变体是纯合的。我们的近亲参与者中的致病基因与非近亲人群报道的基因以及其他近亲人群报道的基因明显不同。为了正确诊断近亲人群的综合征性糖尿病,可能有必要重新评估诊断标准,并包括其他表型特征,如身材矮小和肝脾肿大.
OBJECTIVE: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre
study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and
study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity.
METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing.
RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes.
CONCLUSIONS: This unique single-centre
study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.