非综合征型白化病家系基因分析及产前基因诊断的研究
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摘要
目的①了解中国人群非综合征型白化病致病基因的主要基因类型、突变方式和突变位点的分布特征,探讨白化病的临床表型与基因类型的相关性,建立适合我国白化病患者的基因诊断方法和产前基因诊断方法。②探讨胎儿镜和基因检测两种产前诊断方法在临床上的应用价值,建立适合我国白化病人群的产前诊断方法。
方法①收集26个无血缘关系白化病家系DNA标本共84份(其中2个家系仅收集到亲代DNA标本),包括夫妇双方和(或)先证者外周血DNA标本64份、胎儿羊水细胞DNA标本19份、绒毛DNA标本1份。通过先证者的临床表型将26个家系初分为OCAlA型19个,OCA2型7个。针对可能的基因类型进行家系各成员DNA标本PCR-SSCP检测,结合直接测序法检测家系OCA1、OCA2、OCA3和OCA4四种非综合征型白化病突变基因。分析其中25个家系白化病突变基因与临床表型的相关性。分析其中23个家系亲代与子代突变基因的遗传方式及产前基因诊断的可行性。②对要求胎儿镜检查的家系中的14个随访至妊娠结局,以胎儿或新生儿表型是否正常为诊断金标准,比较胎儿镜与产前基因检测两种诊断方法的优缺点。
结果①26个家系52个预期致病等位基因中,47个等位基因检出致病性突变或新突变,突变的检出率为90%(47/52)。其中25个家系被分别确诊为19个OCA1,4个OCA4,2个OCA2。另外1个家系四种OCA基因类型均未检测到突变。19个OCA1共检测到23种突变,15种是已报道的致病性突变,8种是可疑新突变(C100P,C100T,R212T,T235G,R299C,G506L,1348 insGG,IVS2-17insAC),有待进一步确认;错义突变(15/23)是主要的突变方式;插入突变P930insC(7/38)和错义突变R299H(6/38)出现频率较高。4个OCA4检测到6种突变,5种是可疑新突变(G110A,L151S,A160G,Y266X,1-6del gtggccatgg),其中错义突变4种,无义突变1种,缺失突变1种。2个OCA2检测到3种错义突变,均为可疑新突变(T450L,A455G,L727P)。临床上初分为OCA1A白化病患者,其表型与基因类型的符合率为84%;初分为OCA2患者,其表型与基因类型的符合率仅为29%;OCA1B、OCA2、OCA4三种基因型的临床表型间相互交叉。通过家系分析表明,22个家系44个突变等位基因均以隐性遗传的方式传给子代,符合孟德尔遗传规律。1个家系胎儿携带突变基因与杂合子父亲一致,没有携带母方的白化病基因,但生后表型为“白化病儿”,与隐性遗传规律似不相符,其原因有待进一步探讨。②14个家系中胎儿镜检查的诊断符合率92%,产前基因检测的诊断符合率为100%,产前基因诊断的准确性更高。
结论①26个白化病家系突变基因分析结果提示,OCA1可能是我国主要的基因类型,其中插入突变P930insC和错义突变R299H可能是中国人群的主要突变方式。PCR-SSCP结合直接测序法可以检测出90%以上的基因突变,是适合我国白化病患者的基因诊断方法。②在分析家系白化病突变基因的基础上进行产前基因诊断是可行的,同传统的胎儿镜诊断方法比较,产前基因诊断准确性更高,但基因诊断不能完全替代胎儿镜检查。对于检测不到家系致病性突变基因,胎儿镜仍可作为妊娠中期重要的补充诊断手段。
Objective 1) To establish the relative prevalence of different genotypes and gene mutations of nonsyndromic OCA among Chinese families.2) To investigate the values of fetoscopy and gene mutation detection in prenatal diagnosis of OCA.
Methods 1) We collected 83 samples of genomic DNA,including the proband, parents and fetus,from 26 non-consanguineous OCA families for prenatal genetic counseling.We also collected the clinical phenotypes of the probands.Mutations of the TYR,P,MATP and TYRP1 genes among family members were extensively screened by using PCR-SSCP coupled with direct sequencing.The frequencies of mutational alleles as well as correlations between genotype and phenotype of the probands were analyzed. 2) Prenatal diagnosis of OCA were performed among 14 families by using fetoscopy and genetic analysis.The advantages and disadvantages of the two different prenatal diagnostic methods were evaluated.
Results 1) 47 out of 52(90%) allelic mutations were detected.Among the 26 Chinese families,72%(19/26) had OCA1,8%(2/26) had OCA2,none had OCA3, 16%(4/26) had OCA4,and 4%(1/26) had no detectable pathologic mutations in any of the genes studied.We identified 23 different TYR mutations in 19 families,5 different P mutations in 2 families,and 6 different MATP mutations in 4 families.Among 19 OCA1 families,P930insC and R299H were present in 7 out of 38 alleles and 6 out or 38 alleles respectively,which were the most frequent mutations in Chinese TYR gene. We also identified 8 novel TYR gene mutations(C100P,C100T,R212T,T235G,R299C, G506L,1348 insGG,ⅣS2-17insAC),3 novel P gene mutations(T450L,A455G, L727P) and 5 novel MATP mutations(G110A,L151S,A160G,Y266X,1-6del gtggccatgg ) which have not been reported in the literatures.84%of OCA1A and only 29%of OCA2 clinically diagnosed were confirmed by the molecular results.The clinical appearance overlaps between different OCA types.2) In 14 families for prenatal diagnosis of OCA,fetoscopy showed 92%confirm rate while genetic analysis showed 100%confirm rate.
Conclusions Genetic analysis in 26 Chinese nonsyndromic albinism families showed that OCA1 may be the major type of Chinese OCA.P930insC and R299H may be the most frequent mutational alleles.Prenatal diagnosis are possible when the disease causing mutations have been identified in the family.Compared with traditional fetoscopy diagnosis,prenatal genetic diagnosis is more accurate.
方法①收集26个无血缘关系白化病家系DNA标本共84份(其中2个家系仅收集到亲代DNA标本),包括夫妇双方和(或)先证者外周血DNA标本64份、胎儿羊水细胞DNA标本19份、绒毛DNA标本1份。通过先证者的临床表型将26个家系初分为OCAlA型19个,OCA2型7个。针对可能的基因类型进行家系各成员DNA标本PCR-SSCP检测,结合直接测序法检测家系OCA1、OCA2、OCA3和OCA4四种非综合征型白化病突变基因。分析其中25个家系白化病突变基因与临床表型的相关性。分析其中23个家系亲代与子代突变基因的遗传方式及产前基因诊断的可行性。②对要求胎儿镜检查的家系中的14个随访至妊娠结局,以胎儿或新生儿表型是否正常为诊断金标准,比较胎儿镜与产前基因检测两种诊断方法的优缺点。
结果①26个家系52个预期致病等位基因中,47个等位基因检出致病性突变或新突变,突变的检出率为90%(47/52)。其中25个家系被分别确诊为19个OCA1,4个OCA4,2个OCA2。另外1个家系四种OCA基因类型均未检测到突变。19个OCA1共检测到23种突变,15种是已报道的致病性突变,8种是可疑新突变(C100P,C100T,R212T,T235G,R299C,G506L,1348 insGG,IVS2-17insAC),有待进一步确认;错义突变(15/23)是主要的突变方式;插入突变P930insC(7/38)和错义突变R299H(6/38)出现频率较高。4个OCA4检测到6种突变,5种是可疑新突变(G110A,L151S,A160G,Y266X,1-6del gtggccatgg),其中错义突变4种,无义突变1种,缺失突变1种。2个OCA2检测到3种错义突变,均为可疑新突变(T450L,A455G,L727P)。临床上初分为OCA1A白化病患者,其表型与基因类型的符合率为84%;初分为OCA2患者,其表型与基因类型的符合率仅为29%;OCA1B、OCA2、OCA4三种基因型的临床表型间相互交叉。通过家系分析表明,22个家系44个突变等位基因均以隐性遗传的方式传给子代,符合孟德尔遗传规律。1个家系胎儿携带突变基因与杂合子父亲一致,没有携带母方的白化病基因,但生后表型为“白化病儿”,与隐性遗传规律似不相符,其原因有待进一步探讨。②14个家系中胎儿镜检查的诊断符合率92%,产前基因检测的诊断符合率为100%,产前基因诊断的准确性更高。
结论①26个白化病家系突变基因分析结果提示,OCA1可能是我国主要的基因类型,其中插入突变P930insC和错义突变R299H可能是中国人群的主要突变方式。PCR-SSCP结合直接测序法可以检测出90%以上的基因突变,是适合我国白化病患者的基因诊断方法。②在分析家系白化病突变基因的基础上进行产前基因诊断是可行的,同传统的胎儿镜诊断方法比较,产前基因诊断准确性更高,但基因诊断不能完全替代胎儿镜检查。对于检测不到家系致病性突变基因,胎儿镜仍可作为妊娠中期重要的补充诊断手段。
Objective 1) To establish the relative prevalence of different genotypes and gene mutations of nonsyndromic OCA among Chinese families.2) To investigate the values of fetoscopy and gene mutation detection in prenatal diagnosis of OCA.
Methods 1) We collected 83 samples of genomic DNA,including the proband, parents and fetus,from 26 non-consanguineous OCA families for prenatal genetic counseling.We also collected the clinical phenotypes of the probands.Mutations of the TYR,P,MATP and TYRP1 genes among family members were extensively screened by using PCR-SSCP coupled with direct sequencing.The frequencies of mutational alleles as well as correlations between genotype and phenotype of the probands were analyzed. 2) Prenatal diagnosis of OCA were performed among 14 families by using fetoscopy and genetic analysis.The advantages and disadvantages of the two different prenatal diagnostic methods were evaluated.
Results 1) 47 out of 52(90%) allelic mutations were detected.Among the 26 Chinese families,72%(19/26) had OCA1,8%(2/26) had OCA2,none had OCA3, 16%(4/26) had OCA4,and 4%(1/26) had no detectable pathologic mutations in any of the genes studied.We identified 23 different TYR mutations in 19 families,5 different P mutations in 2 families,and 6 different MATP mutations in 4 families.Among 19 OCA1 families,P930insC and R299H were present in 7 out of 38 alleles and 6 out or 38 alleles respectively,which were the most frequent mutations in Chinese TYR gene. We also identified 8 novel TYR gene mutations(C100P,C100T,R212T,T235G,R299C, G506L,1348 insGG,ⅣS2-17insAC),3 novel P gene mutations(T450L,A455G, L727P) and 5 novel MATP mutations(G110A,L151S,A160G,Y266X,1-6del gtggccatgg ) which have not been reported in the literatures.84%of OCA1A and only 29%of OCA2 clinically diagnosed were confirmed by the molecular results.The clinical appearance overlaps between different OCA types.2) In 14 families for prenatal diagnosis of OCA,fetoscopy showed 92%confirm rate while genetic analysis showed 100%confirm rate.
Conclusions Genetic analysis in 26 Chinese nonsyndromic albinism families showed that OCA1 may be the major type of Chinese OCA.P930insC and R299H may be the most frequent mutational alleles.Prenatal diagnosis are possible when the disease causing mutations have been identified in the family.Compared with traditional fetoscopy diagnosis,prenatal genetic diagnosis is more accurate.
引文
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34 Witkop CJ, Quevedo WC, Fitzpatrick, TB. Albinism in The Metabolic Basis of Inherited Disease 1978 4th ed. Edited by JB Stanbury, JB Wyngarden, DS Fredrickson. New York, McGraw-Hill, pp 283-316,
35 Birbeck, MSC, Barnicot, NA. Electron microscopy of pigment formation in human hair follicles. Pigment Cell Biology. 1959, Edited by M Gordon. New York, Academic,pp549-581.
36 Haynes, ME, Robertson, E. Can oculocutaneous albinism be diagnosed prenatally?Prenatal Diagnosis, 1981,1: 85-89.
37 Eady RA, Gunner DB, Garner A, Rodeck CH. Prenatal Diagnosis of Oculocutaneous Albinism by Electron Microscopy of Fetal Skin. J Invest Dermatol, 1983, 80:210-2.
38 Gershoni-Baruch R, Benderly A, Brandes JM, Gilhar A. Dopa reaction test in hair bulbs of fetuses and its application to the prenatal diagnosis of albinism. J Am Acad Dermatol, 1991,24:220-2.
39 Shimizu H, Ishiko A, Kikuchi A, Akiyama M,et al.Prenatal diagnosis of tyrosinase-negative oculocutaneous albinism by an electron microscopic dopa reaction test of fetal skin. Prenat Diagn, 1994,14:442-50.
40 Wu Y, Sun N,Wang F. Antenatal diagnosis of albinism fetuses by fetoscopy.Zhonghua Fu Chan Ke Za Zhi,1998,33:482-483.
41 Tomita Y,Takeda A,Okinaga S, Tagami H,et al. Human oculocutaneous albinism caused by single base insertion in thetyrosinase gene. Biochem Biophys Res Commun,1989, 164:990-6.
42 Shimizu H,Niizeki H,Suzumori K,et al. Prenatal diagnosis of oculocutaneous Albinism by analysis of the fetal tyrosinase gene. J Invest Dermatol, 1994,103:104-106.
43 Falik-Borenstein TC, Holmes SA, Borochowitz Z, Levin A,et al. DNA-based carrier detection and prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA1A). Prenat Diagn, 1995, 15:345-9.
44 Lee ST, Park SK, Lee H, Lee JS,et al. DNA-based prenatal diagnosis of a Korean family with tyrosinase-related oculocutaneous albinism (OCA1).Jpn J Hum Genet,1997,42:499-505.
45 Rosenmann E, Rosenmann A, Ne'eman Z, Lewin A, et al. Prenatal diagnosis of oculocutaneous albinism type I: review and personal experience. Pediatr Dev Pathol,1999,2:404-14.
46 Yao-Yuan Hsieh, Jer-Yuarn Wu, Chi-Chen Chang, Fuu-Jen Tsai. Prenatal diagnosis of oculocutaneous albinism two mutations located at the same allele Prenat Diagn,2001;21:200-201.
47 李洪义,吴维青,郑辉,段红蕾,等.眼皮肤白化病Ⅰ型产前基因诊断.中华医学遗传学杂志,2006,23:280-282.
48 Hongyi L,Haiyun W,Hui Z,Qing W,et al.Prenatal diagnosis of oculocutaneous albinism type Ⅱ and novel mutations in two Chinese families.Prenat Diagn,2007,27:502-506.
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29 DePinho RA, Kaplan KL. The Hermansky-Pudlak syndrome. Report of three cases and review of pathophysiology and management considerations. Medicine (Baltimore) 1985,64: 192-202.
30 Fukai K, Ishii M, Kadoya A, Chanoki M, et al. Chediak-Higashi syndrome: report of a case and review of the Japanese literature. J Dermatol, 1993, 20: 231-237.
31 Mancini AJ, Chan LS, Paller AS. Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature. J Am Acad Dermatol, 1998, 38:295-300.
32 Kugelman TP,Van Scott EJ. Tyrosinase activity in melanocytes of human albinos. J Invest Dermatol, 1961, 37:73-6.
33 Birbeck, M.S.C, Barnicot, N. A. Electron microscope studies on pigment formation in human, hair follicles. In: Pigment Cell Biology, 1959,p. 548-559.
34 Witkop CJ, Quevedo WC, Fitzpatrick, TB. Albinism in The Metabolic Basis of Inherited Disease 1978 4th ed. Edited by JB Stanbury, JB Wyngarden, DS Fredrickson. New York, McGraw-Hill, pp 283-316,
35 Birbeck, MSC, Barnicot, NA. Electron microscopy of pigment formation in human hair follicles. Pigment Cell Biology. 1959, Edited by M Gordon. New York, Academic,pp549-581.
36 Haynes, ME, Robertson, E. Can oculocutaneous albinism be diagnosed prenatally?Prenatal Diagnosis, 1981,1: 85-89.
37 Eady RA, Gunner DB, Garner A, Rodeck CH. Prenatal Diagnosis of Oculocutaneous Albinism by Electron Microscopy of Fetal Skin. J Invest Dermatol, 1983, 80:210-2.
38 Gershoni-Baruch R, Benderly A, Brandes JM, Gilhar A. Dopa reaction test in hair bulbs of fetuses and its application to the prenatal diagnosis of albinism. J Am Acad Dermatol, 1991,24:220-2.
39 Shimizu H, Ishiko A, Kikuchi A, Akiyama M,et al.Prenatal diagnosis of tyrosinase-negative oculocutaneous albinism by an electron microscopic dopa reaction test of fetal skin. Prenat Diagn, 1994,14:442-50.
40 Wu Y, Sun N,Wang F. Antenatal diagnosis of albinism fetuses by fetoscopy.Zhonghua Fu Chan Ke Za Zhi,1998,33:482-483.
41 Tomita Y,Takeda A,Okinaga S, Tagami H,et al. Human oculocutaneous albinism caused by single base insertion in thetyrosinase gene. Biochem Biophys Res Commun,1989, 164:990-6.
42 Shimizu H,Niizeki H,Suzumori K,et al. Prenatal diagnosis of oculocutaneous Albinism by analysis of the fetal tyrosinase gene. J Invest Dermatol, 1994,103:104-106.
43 Falik-Borenstein TC, Holmes SA, Borochowitz Z, Levin A,et al. DNA-based carrier detection and prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA1A). Prenat Diagn, 1995, 15:345-9.
44 Lee ST, Park SK, Lee H, Lee JS,et al. DNA-based prenatal diagnosis of a Korean family with tyrosinase-related oculocutaneous albinism (OCA1).Jpn J Hum Genet,1997,42:499-505.
45 Rosenmann E, Rosenmann A, Ne'eman Z, Lewin A, et al. Prenatal diagnosis of oculocutaneous albinism type I: review and personal experience. Pediatr Dev Pathol,1999,2:404-14.
46 Yao-Yuan Hsieh, Jer-Yuarn Wu, Chi-Chen Chang, Fuu-Jen Tsai. Prenatal diagnosis of oculocutaneous albinism two mutations located at the same allele Prenat Diagn,2001;21:200-201.
47 李洪义,吴维青,郑辉,段红蕾,等.眼皮肤白化病Ⅰ型产前基因诊断.中华医学遗传学杂志,2006,23:280-282.
48 Hongyi L,Haiyun W,Hui Z,Qing W,et al.Prenatal diagnosis of oculocutaneous albinism type Ⅱ and novel mutations in two Chinese families.Prenat Diagn,2007,27:502-506.