Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark.
Diabetes Care. 2013 Mar;36(3):505-12. doi: 10.2337/dc12-0700. Epub 2012 Nov 12.
Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.
The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.
The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.
There is yet no clear genotype-epigenotype-phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.
短暂性新生儿糖尿病 1 型（TNDM1）是出生时发病的最常见糖尿病病因。大约 5%的病例归因于隐性 ZFP57 突变，导致 TNDM 基因座和其他印迹基因座（HIL）的低甲基化。这对患者护理具有重要意义，因为它会影响表型和家族的复发风险。我们已经确定了前 10 个具有 ZFP57 突变的家族的基因型、表型和表型，以提醒卫生专业人员注意这种新描述的糖尿病遗传亚群。
通过 TNDM1 诊断测试确定了 10 个具有 ZFP57 突变的家庭（14 个纯合子/复合杂合子个体）。对先证者及其亲属进行 ZFP57 测序，并确定多个母系和父系印迹基因座的甲基化水平。获取医疗和家族史，并进行临床检查。
先证者的关键临床特征是短暂性新生儿糖尿病、宫内生长迟缓、巨舌、心脏缺陷和发育迟缓。然而，发现两个无糖尿病和正常智力的纯合子亲属表明表型可能非常多变。表型总是包括 TNDM1 基因座的完全去甲基化，以及其他母系印迹基因座的差异去甲基化的可重复组合，包括组织嵌合体。
目前尚无法明确基因型-表型-表型相关性来解释可变的临床表现，这导致难以预测受影响个体的预后。然而，许多病例的表型比其他 TNDM1 病因更为严重。需要进一步的病例和全球表观遗传学检测来阐明这一点。
