圆锥动脉干畸形遗传学研究
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摘要
第一部分 非综合征性圆锥动脉干畸形中染色体22q11.2缺失调查
[目的] 调查中国人非综合征性圆锥动脉干畸形患者染色体22q11.2微缺失发生情况。
[方法] 运用荧光原位杂交方法对36名非综合征性圆锥动脉干畸形患儿血液标本染色体22q11.2微缺失进行检查，其中男性23例、女性13例，年龄2.74±2.50岁(0.03-11.00岁)，病种为法乐氏四联征21例、右室双出口9例、先天性校正性大动脉转位1例、肺动脉闭锁合并室间隔缺损1例、完全性大动脉转位4例。探针为N25／N85A3探针。
[结果] 3名患儿(8.33％)存在染色体22q11.2微缺失，其中2例为法乐氏四联征，1例为右心室双出口合并肺动脉狭窄。
[结论] 染色体22q11.2微缺失为部分非综合征性圆锥动脉干畸形患者的致病原因。
第二部分 短串联重复序列基因分型行22q11.2缺失调查的方法学研究
[目的] 研究短串联：重复序列基因分型染色体22q11.2微缺失筛查方法的可行性。
[方法] 研究对象同第一部分。选取22q11.2中D22S1638、D22S1648、D22S941、D22S944、D22S1623、D22S264、D22S311、D22S1709等8个短串联重复序列，通过PCR方法对该8个短串联重复序列进行基因分型。计算各短串联重复序列杂合度和纯合度以及按杂合度大小依次引入短串联重复序列后不同短串联重复序列组合纯合状态发生率和与FISH相比染色体22q11.2微缺失诊断特异性。
[结果] 各短串联重复序列杂合度、纯合度分别为：D22S1638 0.3333 0.6667、D22S1648 0.4848 0.5152、D22S941 0.3333 0.6667、D22S944 0.2424 0.7576、D22S1623 0.4545 0.5455、D22S264 0.6061 0.3939、D22S311 0.4545 0.5455、D22S1709 0.0606 0.9394；按杂合度大小依次引入短串联重复序列D22S264、
Section 1 22q11.2 Deletion In Patients With Conotruncal Heart Defects
Objective: To study the incidence of chromosome 22q11.2 deletion in Chinese pediatric non-syndromic conotruncal heart defects patients.
Methods: A total of 36 Chinese pediatric non-syndromic conotruncal heart defects patient (21 with tetralogy of fallot, 9 with double outlet right ventricle, 1 with pulmonary artery atresia with ventricular septal defect, 1 with congenitally corrected transposition of the great arteries and 4 with transposition of the great arteries), 13 females and 23 male ranging in age from 0.03 to 11 years, were included in our study. We did fluorescence in-situ hybridization with N25/N85A3 probe to find the chromosome 22q11.2 deletion in peripheral blood cells of patients.
Results: 3 patients (8. 33%), 2 with tetralogy of fallot and 1 with double outlet right ventricle, have chromosome 22q11.2 deletion.
Conclusion: Chromosome 22q11.2 deletion is an important cause of non-syndromic conotruncal heart defects.
Section 2
Genotyping Of Short Tandem Repeat In Detection Of 22q11.2
Deletion
Objective: To explore an economical and efficient approach for molecular detection of chromosome 22q11.2 deletion.
[目的] 调查中国人非综合征性圆锥动脉干畸形患者染色体22q11.2微缺失发生情况。
[方法] 运用荧光原位杂交方法对36名非综合征性圆锥动脉干畸形患儿血液标本染色体22q11.2微缺失进行检查，其中男性23例、女性13例，年龄2.74±2.50岁(0.03-11.00岁)，病种为法乐氏四联征21例、右室双出口9例、先天性校正性大动脉转位1例、肺动脉闭锁合并室间隔缺损1例、完全性大动脉转位4例。探针为N25／N85A3探针。
[结果] 3名患儿(8.33％)存在染色体22q11.2微缺失，其中2例为法乐氏四联征，1例为右心室双出口合并肺动脉狭窄。
[结论] 染色体22q11.2微缺失为部分非综合征性圆锥动脉干畸形患者的致病原因。
第二部分 短串联重复序列基因分型行22q11.2缺失调查的方法学研究
[目的] 研究短串联：重复序列基因分型染色体22q11.2微缺失筛查方法的可行性。
[方法] 研究对象同第一部分。选取22q11.2中D22S1638、D22S1648、D22S941、D22S944、D22S1623、D22S264、D22S311、D22S1709等8个短串联重复序列，通过PCR方法对该8个短串联重复序列进行基因分型。计算各短串联重复序列杂合度和纯合度以及按杂合度大小依次引入短串联重复序列后不同短串联重复序列组合纯合状态发生率和与FISH相比染色体22q11.2微缺失诊断特异性。
[结果] 各短串联重复序列杂合度、纯合度分别为：D22S1638 0.3333 0.6667、D22S1648 0.4848 0.5152、D22S941 0.3333 0.6667、D22S944 0.2424 0.7576、D22S1623 0.4545 0.5455、D22S264 0.6061 0.3939、D22S311 0.4545 0.5455、D22S1709 0.0606 0.9394；按杂合度大小依次引入短串联重复序列D22S264、
Section 1 22q11.2 Deletion In Patients With Conotruncal Heart Defects
Objective: To study the incidence of chromosome 22q11.2 deletion in Chinese pediatric non-syndromic conotruncal heart defects patients.
Methods: A total of 36 Chinese pediatric non-syndromic conotruncal heart defects patient (21 with tetralogy of fallot, 9 with double outlet right ventricle, 1 with pulmonary artery atresia with ventricular septal defect, 1 with congenitally corrected transposition of the great arteries and 4 with transposition of the great arteries), 13 females and 23 male ranging in age from 0.03 to 11 years, were included in our study. We did fluorescence in-situ hybridization with N25/N85A3 probe to find the chromosome 22q11.2 deletion in peripheral blood cells of patients.
Results: 3 patients (8. 33%), 2 with tetralogy of fallot and 1 with double outlet right ventricle, have chromosome 22q11.2 deletion.
Conclusion: Chromosome 22q11.2 deletion is an important cause of non-syndromic conotruncal heart defects.
Section 2
Genotyping Of Short Tandem Repeat In Detection Of 22q11.2
Deletion
Objective: To explore an economical and efficient approach for molecular detection of chromosome 22q11.2 deletion.
引文
[1] Driscoll DA, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 1992; 50: 924-933.
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[3] Burn J, Takao A, Wilson D, et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet 1993; 30: 822-824.
[4] Wamagishi H. The 22q11.2 deletion syndrome. Keio J Med 2002; 51: 77-88.
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[6] Shaikh T H, et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 2000; 9: 489-501.
[7] Heller J. CATCH22. 1st eds London: Jonathan Cape 1992: 1-12.
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[10] Matsuoka R, Takao A, Kimura M, et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22911.2. Am J Med Genet 1994; 53: 285-289.
[11] Driscoll DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Cenet 1993; 30: 813-817.[12] Desmaze C, Scambler P, Prieur M, et al. Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization. Hum Genet 1994; 90: 663-665.
[13] Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997; 34: 798-804.
[14] Jawad AF, McDonald-McGinn DM, Zackai E, et al. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 2001, 139: 715-723.
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[3] Driscoll DA, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 1992; 50: 924-933.
[4] Scambler PJ, Kelly D, Lindsay E, et al. Velocardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992; 339: 1138-1139.
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[9] Elder DA, Kaiser-Rogers K, Aylsworth AS, et al. Type I diabetes mellitus in a 682 Allergy, immunology, and related disorders patient with chromosome 22q11.2 deletion syndrome. Am J Med Genet 2001, 101: 17-19.
[10] Kawame H, Adachi M, Tachibana K, et al. Graves' disease in patients with 22qll.2 deletion. J Pediatr 2001, 139:892-895.
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[20] Moss EM, Batshaw ML, Solot CB, et al. Psychoeducational profile of the 22qll.2 microdeletion: A complex pattern. J Pediatr 1999; 134:193-198.
[21] Karayiorgou M, Morris MA, Morrow B, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22qll. Proc Natl Acad Sci USA 1995; 92: 7612-7616.
[22] Sugama S, Namihira T, Matsuoka R, et al. Psychiatric inpatients and chromosome deletions within 22qll. 2. J Neurol Neurosurg Psychiatry 1999;67: 803-806.
[23] Lindsay E A. Chromosome microdeletions: dissecting del22qll syndrome.Nat Rev Genet 2001; 2: 858-868.
[24] Shaikh T H, et al. Chromosome 22-specific low copy repeats and the 22qll.2 deletion syndrome: genomic organization and deletion endpointanalysis. Hum Mol Genet 2000; 9: 489-501.
[25] Lindsay E A, et al. Submicroscopic deletions at 22qll.2: variability of the clinical picture and delineation of a commonly deleted region. Am J Med Genet 1995; 56: 191-197.
[26] Gong W, et al. A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22qll. Hum Mol Genet 1996; 5: 789-800.
[27] Carlson C, et al. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet 1997; 61: 620-629.
[28] Matsuoka R, et al. Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome. Hum Genet 1998; 103: 70-80.
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[41] Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, TBX1. Nat Genet 2001; 27: 286-291.
[42] Gong W, Gottlieb S, Collins J, et al. Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 2001; 38: E45.
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[47] Heller J. CATCH22. 1st eds London: Jonathan Cape 1992: 1-12.
[48] Greenberg F. DiGeorge syndrome: an historical review of clinical and cytogenetic features. J Med Genet 1993; 30: 803-806.
[49] Goldberg R, Motzkin B, Marion R, et al. Velo-cardio-facial syndrome:??a review of 120 patients. Am J Med Genet, 1993; 45: 313-319.
[50] Matsuoka R, Takao A, Kimura M, et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am J Med Genet 1994; 53: 285-289.
[51] Wilson DI, Bum J, Scambler P, et al. DiGeorge syndrome: part of CATCH 22. J Med Genet 1993: 852-856.
[52] Driscoll DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet 1993; 30: 813-817.
[53] Desmaze C, Seambler P, Prieur M, et al. Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization. Hum Genet 1994; 90: 663-665.
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