CFTR基因变异致囊性纤维化1例报告并文献复习
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摘要
目的探讨中国人群囊性纤维化基因型与临床表型的关系。方法回顾分析2015年3月收治的1例囊性纤维化患儿的临床资料,并复习相关文献。结果患儿,女,生后不久开始出现反复咳嗽、咳痰,肺部感染。9岁就诊时有重度营养不良,杵状指(趾),副鼻窦区压痛,双肺散在湿罗音;实验室检查提示胰腺炎;影像学检查提示合并鼻窦炎及支气管扩张;全外显子基因组测序示CFTR基因复合杂合变异,等位基因1,c.1766+5G>T(NM_000492.3)剪接突变;等位基因2,c.2805delA:p.L935fs(NM_000492)移码突变;检出基因型匹配囊性纤维化临床表型。检索建库至2018年7月中国知网、万方及PubMed数据库,以"囊性纤维化"和"基因"为关键词组合检索,共检索到7篇文献,报道9例包含c.1766+5G>T位点变异的囊性纤维化患儿,加上该例共10例。10例患儿均为中国人,且均以反复咳嗽、咳痰等肺部感染为主要表现,多数合并支气管扩张,仅部分合并胰腺功能不全。结论 c.1766+5G>T位点可能是中国人特有的CFTR基因变异位点,与c. 2805 delA:p.L 935 fs变异构成新的复合杂合变异,其临床表型主要以呼吸道感染为主,较少累及消化道。
Objective To explore the relationship between cystic fibrosis genotype and clinical phenotype in Chinese population. Method The clinical data of cystic fibrosis in a child admitted in March 2015 were retrospectively analyzed, and the related literature was reviewed. Results A girl began to develop recurrent cough and expectoration and pulmonary infection shortly after birth. At the age of 9, the patient was found to have severe malnutrition, clubbing fingers(toes), tenderness in the paranasal sinus area, and scattered rales in both lungs. Laboratory examination suggested pancreatitis; imaging examination suggested sinusitis and bronchiectasis. Whole exon genome sequencing detected complex heterozygous mutations of CFTR gene including splicing mutation of c. 1766 + 5 G>T(NM_ 000492. 3) in allele 1 and frameshift mutation of c. 2805 delA:p.L 935 fs(NM_000492) in allele 2, which matched the clinical phenotype of cystic fibrosis. The databases of CNKI, Wanfang and PubMed were searched with "cystic fibrosis" and "gene" as key words up to July 2018. A total of 7 articles were retrieved and 9 cases of cystic fibrosis with c.1766+5 G>T mutations were reported. Including 1 case in this study, a total of 10 cases of cystic fibrosis were reported. All the 10 children were Chinese and the main manifestations were recurrent cough and expectoration. Most of them were complicated with bronchiectasis, and only some of them were complicated with pancreatic insufficiency. Conclusion The c. 1766 + 5 G>T locus may be the unique mutation site of CFTR gene in China. It is a new complex heterozygous variant with c. 2805 delA:p.L 935 fs mutation. Its clinical phenotype is mainly respiratory tract infection and digestive tract is rarely involved.
Objective To explore the relationship between cystic fibrosis genotype and clinical phenotype in Chinese population. Method The clinical data of cystic fibrosis in a child admitted in March 2015 were retrospectively analyzed, and the related literature was reviewed. Results A girl began to develop recurrent cough and expectoration and pulmonary infection shortly after birth. At the age of 9, the patient was found to have severe malnutrition, clubbing fingers(toes), tenderness in the paranasal sinus area, and scattered rales in both lungs. Laboratory examination suggested pancreatitis; imaging examination suggested sinusitis and bronchiectasis. Whole exon genome sequencing detected complex heterozygous mutations of CFTR gene including splicing mutation of c. 1766 + 5 G>T(NM_ 000492. 3) in allele 1 and frameshift mutation of c. 2805 delA:p.L 935 fs(NM_000492) in allele 2, which matched the clinical phenotype of cystic fibrosis. The databases of CNKI, Wanfang and PubMed were searched with "cystic fibrosis" and "gene" as key words up to July 2018. A total of 7 articles were retrieved and 9 cases of cystic fibrosis with c.1766+5 G>T mutations were reported. Including 1 case in this study, a total of 10 cases of cystic fibrosis were reported. All the 10 children were Chinese and the main manifestations were recurrent cough and expectoration. Most of them were complicated with bronchiectasis, and only some of them were complicated with pancreatic insufficiency. Conclusion The c. 1766 + 5 G>T locus may be the unique mutation site of CFTR gene in China. It is a new complex heterozygous variant with c. 2805 delA:p.L 935 fs mutation. Its clinical phenotype is mainly respiratory tract infection and digestive tract is rarely involved.
引文
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[11]Chen CH,Chang CC,Yang BY,et al.Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis[J].J Formos Med Assoc,2012,111(10):580-583.
[12]刘亭威,康健.中国人囊性纤维化临床特点分析[J].中国全科医学,2012(24):2807-2810.
[13]Castellani C,Cuppens H,Macek MJ,et al.Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice[J].J Cyst Fibros,2008,7(3):179-196.
[14]Li N,Pei P,Bu DF,et al.A novel CFTR mutation found in a Chinese patient with cystic fibrosis[J].Chin Med J(Engl),2006,119(2):103-109.
[15]徐保平,王昊.儿童囊性纤维化的相关问题[J].中国循证儿科杂志,2015(4):241-244.
[16]Strong TV,Smit LS,Nasr S,et al.Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator(CFTR)gene[J].Hum Mutat,1992,1(5):380-387.
[17]Chu CS,Trapnell BC,Curristin SM,et al.Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis[J].J Clin Invest,1992,90(3):785-790.
[18]Flume PA,Liou TG,Borowitz DS,et al.Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation[J].Chest,2012,142(3):718-724.
[2]Haack A,Aragao GG,Novaes MR.Pathophysiology of cystic fibrosis and drugs used in associated digestive tract diseases[J].World J Gastroenterol,2013,19(46):8552-8561.
[3]Milla CE.Cystic fibrosis in the era of genomic medicine[J].Curr Opin Pediatr,2013,25(3):323-328.
[4]褚佳琳,王莹,钱娟.儿童囊性肺纤维化合并重症肺炎一例[J].中国小儿急救医学,2016(7):501-504.
[5]蔡勇,陈德晖,刘文宽,等.中国囊性纤维化患儿囊性纤维化跨膜传导调节因子基因突变分析[J].中华实用儿科临床杂志,2017(13):1000-1003.
[6]Leung GK,Ying D,Mak CC,et al.CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis[J].Mol Genet Genomic Med,2017,5(1):40-49.
[7]Zielenski J,Markiewicz D,Lin SP,et al.Skipping of exon12 as a consequence of a point mutation(1898+5G-->T)in the cystic fibrosis transmembrane conductance regulator gene found in a consanguineous Chinese family[J].Clin Genet,1995,47(3):125-132.
[8]Wu CL,Shu SG,Zielenski J,et al.Novel cystic fibrosis mutation(2215insG)in two adolescent Taiwanese siblings[J].J Formos Med Assoc,2000,99(7):564-567.
[9]Shen Y,Liu J,Zhong L,et al.Clinical Phenotypes and genotypic spectrum of cystic fibrosis in Chinese children[J].J Pediatr,2016,171:269-276.
[10]Alper OM,Shu SG,Lee MH,et al.Detection of novel CFTR mutations in Taiwanese cystic fibrosis patients[J].JFormos Med Assoc,2003,102(5):287-291.
[11]Chen CH,Chang CC,Yang BY,et al.Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis[J].J Formos Med Assoc,2012,111(10):580-583.
[12]刘亭威,康健.中国人囊性纤维化临床特点分析[J].中国全科医学,2012(24):2807-2810.
[13]Castellani C,Cuppens H,Macek MJ,et al.Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice[J].J Cyst Fibros,2008,7(3):179-196.
[14]Li N,Pei P,Bu DF,et al.A novel CFTR mutation found in a Chinese patient with cystic fibrosis[J].Chin Med J(Engl),2006,119(2):103-109.
[15]徐保平,王昊.儿童囊性纤维化的相关问题[J].中国循证儿科杂志,2015(4):241-244.
[16]Strong TV,Smit LS,Nasr S,et al.Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator(CFTR)gene[J].Hum Mutat,1992,1(5):380-387.
[17]Chu CS,Trapnell BC,Curristin SM,et al.Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis[J].J Clin Invest,1992,90(3):785-790.
[18]Flume PA,Liou TG,Borowitz DS,et al.Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation[J].Chest,2012,142(3):718-724.