Aicardi-Goutières syndrome type 7 in a Chinese child: A case report.

BACKGROUND: IFIH1 is a protein-coding gene. Disorders associated with IFIH1 include Aicardi-Goutières syndrome (AGS) type 7 and Singleton-Merten syndrome type 1. Related pathways include RIG-I/MDA5-mediated induction of the interferon (IFN)-α/ß pathway and the innate immune system. AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. In infancy, most patients present with psychomotor retardation, axial hypotonia, spasticity, and brain imaging changes Laboratory assessments showed increased IFN-α activity with upregulation of IFN signaling and IFN-stimulated gene expression. Some patients develop normally in the early stage, and then have episodic neurological deficits. CASE SUMMARY: The 5-year-old girl presented with postpartum height and weight growth retardation, language retardation, brain atrophy, convulsions, and growth hormone deficiency. DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation. Heterozygous mutations in the IFIH1 gene were found. Physical examination at admission found that language development was delayed, the reaction to name calling was average, there was no communication with people, but there was eye contact, no social smile, and no autonomous language. However, the child had rich gesture language and body language, could understand instructions, had bad temper. When she wants to achieve something, she starts crying or shouting. Cardiopulmonary examination showed no obvious abnormality, and abdominal examination was normal. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes exist, but pathological reflexes were not elicited. CONCLUSION: We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7, which expanded the mutational spectrum of the IFIH1 gene.

Case report: Pneumocystis jirovecii pneumonia in a severe case of Aicardi-Goutières syndrome with an IFIH1 gain-of-function mutation mimicking combined immunodeficiency.

Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset progressive encephalopathy caused by mutations leading to overexpression of type I interferon (IFN) and resulting in various clinical phenotypes. A gain-of-function (GOF) mutation in the IFIH1 gene is associated with robust production of type I IFN and activation of the Janus kinase (JAK) signal transducer and activator of the transcription (STAT) pathway, which can cause AGS type 7. We detail the clinical case of an infant who initially presented with Pneumocystis jirovecii pneumonia (PCP), had recurrent respiratory infections, and was later treated with a JAK inhibitor, baricitinib, because of a genetically confirmed GOF mutation in the IFIH1 gene. This spectrum of IFIH1 GOF mutations with overlapping features of hyperinflammation and severe opportunistic infection, which mimics combined immunodeficiency (CID), has not been described before. In this case, therapy with baricitinib effectively blocked IFN-α activation and reduced STAT1 signaling but had no effect on the progression of the neurological disease.

The interferon-induced helicase C domain-containing protein 1 gene variant (rs1990760) as an autoimmune-based pathology susceptibility factor.

PURPOSE: Autoimmune diseases are a group of complex diseases localized in multiple organ systems, with a wide spectrum of symptoms and still unclear causes. The aim of the present study was to analyse a possible association of three autoimmune disabilities - Multiple sclerosis (MS), LADA diabetes and Graves' disease (GD) with single nucleotide polymorphism (SNP; rs1990760) in the IF IH1 gene (also known as a melanoma differentiation-associated protein 5 - MDA5) within the Polish population. An additional goal was also to look for a correlation between this polymorphism and different clinical patient-related factors. MATERIALS AND METHODS: The study population consisted of four groups of 944 unrelated Polish origin Caucasian patients - 324 with GD, 171 with MS, 49 with LADA diabetes and 400 healthy subjects as a control group. The SNP analysis was performed using the allelic discrimination technique. RESULTS & CONCLUSIONS: There were significant associations of risk T allel of the analyzed polymorphism with all studied autoimmune diseases (GDOR = 1.34, p = 7.02e-03; MSOR = 1.36, p = 2.17e-02; LADA - OR = 3.36, p = 8.73e-07). We also found that the frequency of CT and TT genotypes of the rs1990760 IFIH1 gene only in females (with LADA, GD, MS) was significantly higher than those in the female control group (47%, 41% vs 44%, 34%; p = 1.32e-03, p = 4.39e-04; OR = 2.08, 95%CI: (1.33-3.28), OR = 2.29, 95% CI: (1.44-3.65) respectively). Our research has shown significant differences regarding some clinical features (BMI, TRAb, TSH, HbA1C, anti-GAD antibodies) and age at the beginning of the studied autoimmune disabilities. This study showed an association of rs1990760 polymorphism in the IFIH1 gene in the development of GD, LADA diabetes and MS within the Polish population. To our knowledge, this is the first study to investigate the relationship between IFIH1 polymorphisms and the risk of the development of MS and LADA in Poland.

Analysis of chosen polymorphisms rs2476601 a/G - PTPN22, rs1990760 C/T - IFIH1, rs179247 a/G - TSHR in pathogenesis of autoimmune thyroid diseases in children.

BACKGROUND: Autoimmune thyroid diseases are multifactorial diseases with a genetic susceptibility and environmental factors. A potential role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, the interferon-induced helicase domain 1 (IFIH1) gene, the thyroid-stimulating hormone receptor (TSHR) gene polymorphisms on autoimmune thyroid diseases (AITDs) in adults has been established unequivocally, but there is still lack of research articles including group of children. Objective and hypotheses: To estimate the association of polymorphisms of PTPN22, IFIH1 and TSH-R genes with the pre-disposition to Graves' disease (GD) and Hashimoto's thyroiditis (HT) in children. METHODS: The study was performed in 142 patients with GD, 57 with HT and 160 healthy volunteers. The three single-nucleotide polymorphisms (SNPs): rs2476601 - PTPN22, rs1990760 - IFIH1 and rs179247 - TSHR were genotyped by TaqMan SNP genotyping assay using the real-time PCR. RESULTS: Rs2476601 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = .009 with odds ratio [OR] = 2.13). Rs2476601 A alleles were more frequent in patients with HT in comparison to healthy subjects (p = .008, OR = 2.48). Rs1990760 T alleles were more frequent in male patients with GD in comparison to healthy males (p = .003, OR = 3.00). In case of HT patients, rs1990760 T alleles were also more frequent in males compared to healthy subjects (p = .086, OR =2.47). Rs179247 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = 0.039, OR = 1.51). CONCLUSIONS: Rs2476601 A/G, Rs1990760 C/T and Rs179247 A/G polymorphisms could contribute to the development of AITDs in children. The main risk factor for rs2476601 and rs179247 is allele A. In case of rs1990760, the main risk factor is allele T.

A study on the IFIH1 gene polymorphism in children with type 1 diabetes in Tianjin area / 中华内分泌代谢杂志

The blood samples of 102 type 1 diabetic children aged under 15 years and 127 normal children were collected and their genomic DNAs were extracted. The single nucleotide polymorphisms rs1990760 and rs35744605 of interferon induced with helicase C domain 1(IFIH1)gene were detected. The results showed that the allele of IFIH1 rs35744605 in diabetes group and control group was the wild type G allele. The frequency of IFIH1 rs1990760 A allele in diabetes group was higher than that in control group(22. 1％ vs 13. 0％ ,P=0. 015), suggesting that IFIH1 rs1990760 A allele is associated with type 1 diabetes in Tianjin area.