Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Front Endocrinol (Lausanne). 2023 Mar 7;14:1066320. doi: 10.3389/fendo.2023.1066320. eCollection 2023.
-related disorders involve a wide range of clinical phenotypes, including diabetes mellitus and neurodegeneration. Inheritance patterns of pathogenic variants of this gene can be autosomal recessive or dominant, and differences in penetrance present challenges for accurate diagnosis and genetic counselling.
Three probands and one elder brother from three families were systematically evaluated and the clinical data of other family members were collected from the medical history. Whole-exome sequencing was performed on the probands, and RNA sequencing was performed on four patients, their parents with variants, and four gender- and age-matched children with type 1 diabetes mellitus.
There were six patients with diabetes. Dilated cardiomyopathy, a rare manifestation of -related disease, was identified in one patient, along with MRI findings of brain atrophy at age 7 years and 3 months, the earliest age of discovery we know of. Whole-exome sequencing revealed five pathogenic or likely pathogenic variants in the gene, including c.1348dupC (p.His450Profs93), c.1381A>C (p.Thr461pro), c.1329C>G (p.Ser443Arg), c.2081delA (p.Glu694Glyfs16), c.1350-1356delinsGCA (p.His450Glnfs*26), of which 3 variants (c.1348dupC, c.2081delA, c.1350-1356delinsGCA) were novel that have not been previously reported. The differentially expressed genes were mainly associated with immune-related pathways according to the Gene Ontology enrichment analysis of the RNA sequencing data. The exon 1 region of in two patients was not transcribed, while the transcription of the region in their parents was normal.
This study emphasizes the clinical and genetic heterogeneity in patients, even in the same family with variants. MRI evaluation of the brain should be considered when -related disorder is first diagnosed.
-相关疾病涉及广泛的临床表型，包括糖尿病和神经退行性变。该基因的致病性变异的遗传模式可以是常染色体隐性或显性，并且外显率的差异给准确诊断和遗传咨询带来了挑战。
对三个家系的三个先证者和一个哥哥进行了系统评估，并从病史中收集了其他家族成员的临床资料。对先证者进行了全外显子组测序，对四个患者及其携带变异的父母和四个性别和年龄匹配的 1 型糖尿病患者进行了 RNA 测序。
有六名患者患有糖尿病。一名患者被诊断为 -相关疾病的罕见表现，扩张型心肌病，并在 7 岁零 3 个月时发现大脑萎缩的 MRI 表现，这是我们所知的最早发现年龄。全外显子组测序发现 基因中的五个致病性或可能致病性变异，包括 c.1348dupC(p.His450Profs93)、c.1381A>C(p.Thr461pro)、c.1329C>G(p.Ser443Arg)、c.2081delA(p.Glu694Glyfs16)、c.1350-1356delinsGCA(p.His450Glnfs*26)，其中 3 个变异(c.1348dupC、c.2081delA、c.1350-1356delinsGCA)是新的，以前没有报道过。根据 RNA 测序数据的基因本体富集分析，差异表达的基因主要与免疫相关途径有关。两个患者的 基因外显子 1 区域未转录，而其父母的转录区域正常。
本研究强调了即使是同一家庭的 变异患者，临床和遗传也存在异质性。当首次诊断为 -相关疾病时，应考虑进行脑 MRI 评估。
