大动脉炎(TA)是一种影响主动脉及其分支的慢性肉芽肿性炎症性疾病。儿科TA(pTA)可能从出生后6个月到青少年年龄组出现。pTA的遗传学和发病机制尚未完全了解。早期的研究报道了NOD2,XIAP,和STAT1基因在pTA患者中的表达。TA,一种相对罕见的疾病,在地理口袋里更常见,包括印度。我们假设南亚pTA患者,即,那些来自印度次大陆的,可能有涉及一个或多个基因的临床相关和独特的致病变异,尤其是那些与基因驱动的血管疾病有关的疾病,包括自身炎症病理。pTA符合EULAR/PRINTO/PReS分类标准并在基督教医学院儿科风湿病诊所出现临床症状的儿童,Vellore,包括在内。在获得父母或监护人的知情同意以及儿童的同意形式后收集血液样本。使用QiagenDNA提取试剂盒从全血提取DNA。最初,印度人口中的常见变体,即,ADA2c.139G>A;p.Gly47Arg,被筛选,其次是整个外显子组测序。这项研究招募了14名儿童。患者的中位年龄为11岁(4个月-14岁),男女比例为4:10。纳入儿童的Numano分类血管造影子集分布如下:5型(n=7),类型4(n=5),和类型3(n=2)。我们在十个不同的基因中鉴定了新的变异体。这包括经典补体途径基因的变异,即,C2、C3、C6、C7和C9等基因,即,CYBA,SH3BP2,GUCY2C,CTC1、COL5A1和NLPR3。14例患者中有2例具有杂合致病变异;这意味着C3和COL5A1中杂合变异的组合可能导致疾病发展。提示双基因遗传。一名患者在CYBA中具有纯合变体。没有患者被鉴定为具有ADA2变体。全外显子组测序揭示了与高动脉炎儿童疾病发展相关的基因C3、COL5A1和CYBA中罕见变异的组合。关键点•我们发现了经典补体途径基因的新变体,即,C2、C3、C6、C7和C9等基因,即,CYBA,SH3BP2,GUCY2C,CTC1、COL5A1和NLPR3。•14例患者中有2例具有C3和COL5A1的杂合致病变异;这可能对疾病发展有影响。提示双基因遗传。•一名患者在CYBA中具有纯合变体。•没有患者被鉴定为具有ADA2变体。
Takayasu arteritis (TA) is a chronic granulomatous inflammatory disease affecting the aorta and its branches. Paediatric TA (pTA) may present from 6 months after birth till the adolescent age group. Genetics and pathogenesis of pTA are not fully understood. Earlier studies reported monogenic mutation in NOD2, XIAP, and STAT1 genes in patients with pTA. TA, a relatively rare disease, is more common in geographical pockets, including India. We hypothesized that South Asian patients with pTA, namely, those of Indian subcontinent origin, may have clinically relevant and unique pathogenic variants involving one or more genes, especially those linked to genetically driven vasculitic illnesses, including autoinflammatory pathologies. Children with pTA fulfilling EULAR/PRINTO/PReS classification criteria and presenting with clinical symptoms to the Paediatric Rheumatology clinic of Christian Medical College, Vellore, were included. Blood samples were collected after getting informed consent from parents or guardians and assent forms from children. DNA was extracted from whole blood using the Qiagen DNA extraction kit. Initially, the common variant in Indian population, namely, ADA2 c.139G > A; p.Gly47Arg, was screened, followed by whole exome sequencing. Fourteen children were recruited for the
study. Median age of patients was 11 years (4 months-14 years) with a male-to-female ratio of 4:10. Distribution of angiographic subsets by Numano\'s classification of included children were as follows: type 5 (n = 7), type 4 (n = 5), and type 3 (n = 2). We identified novel variants in ten different genes. This include variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. Two of 14 patients have heterozygous pathogenic variants; this implies that combination of heterozygous variants in C3 and COL5A1 might lead to disease development, suggesting digenic inheritance. One patient has a homozygous variant in CYBA. None of the patients were identified to have ADA2 variants. Whole exome sequencing reveals combination of rare variants in genes C3, COL5A1, and CYBA associated with disease development in children with Takayasu Arteritis. Key Points • We identified novel variants in genes of classical complement pathway, namely, C2, C3, C6, C7, and C9, and other genes, namely, CYBA, SH3BP2, GUCY2C, CTC1, COL5A1, and NLPR3. • Two of 14 patients have heterozygous pathogenic variants in C3 and COL5A1; this may have implications in disease development, suggesting digenic inheritance. • One patient has homozygous variant in CYBA. • None of the patients were identified to have ADA2 variants.