Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
Department of Clinical and Laboratory Genetics, Medical University of Lodz, Lodz, Poland.
Pediatr Diabetes. 2022 Sep;23(6):668-674. doi: 10.1111/pedi.13341. Epub 2022 Apr 24.
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.
新生儿糖尿病合并先天性甲状腺功能减退症（NDH）综合征（MIM# 610199）是一种罕见疾病，由 GLIS3 基因的常染色体隐性突变引起。GLIS3 是一种重要的转录因子，既可以作为转录的抑制剂，也可以作为转录的激活剂。迄今为止，已有来自 16 个国家的 22 例 NDH 综合征病例被描述。本文报道了一例患儿在出生后第一周即出现糖尿病，同时患有先天性甲状腺功能减退症、心脏异常和多囊肾病。基因分析显示，患者为 GLIS3 基因两个新的杂合突变 p.Pro444fsdelG（c.1330delC）和 p.His647Arg（c.1940A > G）的携带者，分别来自临床健康的父亲和母亲。生物信息学工具（SIFT、PolyPhen2、PROVEAN 和 SWISS-MODEL）预测 p.His647Arg（c.1940A > G）变异具有很强的有害影响，并干扰了 Kruppel 样锌指结构域。到目前为止，所有描述的 NDH 综合征病例均由 GLIS3 纯合突变引起，这使得该病例成为全球第二个致病性 GLIS3 复合杂合突变病例，具有显著的临床新颖性，并详细描述了观察到的变异与 GLIS3 表达之间的有趣相互作用，GLIS3 似乎是自身调控的。因此，这种破坏性的错义突变可能进一步降低任何剩余功能性等位基因的表达。本病例报告扩展了我们对 GLIS3 突变婴儿的临床表型、治疗方法和结局的认识，并表明需要进一步研究以加深我们对 GLIS3 作用的理解。
