Abstract：
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (MIM# 610199) is a rare disease caused by autosomal recessive mutations in the GLIS3 gene. GLIS3 is an important transcription factor that might acts as both a repressor and activator of transcription. To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described. Herein, we report a child who developed diabetes during the first week of age. Additionally, she suffered from congenital hypothyroidism, cardiac abnormalities, and polycystic kidney disease. Genetic analysis revealed that patient is a carrier of two novel heterozygous mutations, p.Pro444fsdelG (c.1330delC) and p.His647Arg (c.1940A > G) in the GLIS3 gene. Each was inherited from clinically healthy father and mother, respectively. Bioinformatic tools (SIFT, PolyPhen2, PROVEAN and SWISS-MODEL) declared that the p.His647Arg (c.1940A > G) variant has strong detrimental effect and disturbs Kruppel-like zinc finger domain. All but one so far described cases of NDH syndrome have been caused by homozygous of GLIS3, making the described case the second case of pathogenic, compound heterozygosity of GLIS3 worldwide posing substantial clinical novelty and detailing an interesting interplay between the observed variants and GLIS3 expression, which seems to be autoregulated. Hence, the damaging missense mutation may further reduce the expression of any remaining functional alleles. This case report expands our understanding of the clinical phenotype, treatment approaches, and outcome of infants with GLIS3 mutations and indicates the need for further research to deepen our understanding of the role of GLIS3.
摘要：
患有先天性甲状腺功能减退症（NDH）综合征的新生儿糖尿病（MIM＃610199）是由GLIS3基因的常染色体隐性突变引起的罕见疾病。GLIS3是一种重要的转录因子，可能既是转录抑制因子又是转录激活因子。迄今为止,已描述了来自16个家庭和11个国家的22例NDH综合征。在这里，我们报告了一名儿童在出生后的第一周内患上了糖尿病。此外,她患有先天性甲状腺功能减退症,心脏异常,和多囊肾病。遗传分析显示，患者是两个新的杂合突变的携带者，GLIS3基因中的p.Pro444fsdelG(c.133delC)和p.His647Arg(c.1940A>G)。每个都遗传自临床健康的父亲和母亲，分别。生物信息学工具(SIFT，PolyPhen2，PROVEAN和SWISS-MODEL）声明p.His647Arg（c.1940A>G）变体具有很强的有害作用，并干扰了Kruppel样锌指结构域。到目前为止，除了一个描述的NDH综合征病例外，所有病例都是由GLIS3纯合子引起的，使描述的病例成为第二例致病性病例，全球范围内GLIS3的复合杂合性构成了实质性的临床新颖性，并详述了观察到的变体和GLIS3表达之间的有趣相互作用，这似乎是自动调节的。因此，破坏性错义突变可进一步降低任何剩余功能性等位基因的表达。这个病例报告扩大了我们对临床表型的理解，治疗方法,以及具有GLIS3突变的婴儿的结局，并表明需要进一步研究以加深我们对GLIS3作用的理解。
