缺失/重复突变检测技术的评价和诊断策略及一个先天性眼球震颤家系的基因突变检测
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摘要
多重连接探针扩增(Multiplex ligation-dependent probe amplification, MLPA)技术是近年来发展的一项灵敏度较高的相对定量分析技术,利用简单的杂交、连接及PCR扩增反应和电泳分离,于单一反应管内可同时检测多个不同区域核苷酸序列的拷贝数变化。它已成功应用于Duchenne型肌营养不良症(Duchenne muscular dystrophy, DMD)、亚端粒区域微缺失及其他基因缺失和重复导致的智力低下、各类综合征等疾病的检测中。本课题引进MLPA技术用于DMD和威廉斯综合征(Williams Beuren syndrome, WBS)的缺失/重复检测,在此基础上对其进行总结评价,从而创建了更为简便的适于中国患者基因检测的分子诊断策略,使其更易于基层单位的普遍推广应用,获得更大的临床应用价值。
一、Duchenne肌营养不良症
DMD是一种人类常见的致死性X连锁隐性遗传的神经肌肉系统疾病,发病率约为活产男婴的1/3500,约1/3是散发病例。由于抗肌萎缩蛋白基因突变影响dystrophin蛋白在横纹肌组织的表达,导致肢体近端骨骼肌进行性萎缩、无力和腓肠肌假性肥大。致病基因DMD位于Xp21.1-21.3,含79个外显子。该病发生的分子基础包括基因的部分缺失、部分重复及点突变等微小改变。本文首先对116例DMD患者的MLPA结果进行了分析评价,并在统计分析前期380例DMD患者的基因缺失突变谱的基础上,建立了更适合于中国人DMD基因突变检测的多重PCR新体系“5×2+6”,在普通单位尤其是基层,它可作为DMD基因检测的首选方案,而MLPA技术作为补充。两者的联合应用旨在建立更加简便、快速、高效的DMD分子诊断策略。此外,本文亦对中国地区DMD患者的基因缺失/重复突变特点进行了详细而深入的总结探讨。
二、威廉斯综合征
威廉斯综合征是一种少见的遗传性精神发育迟滞性疾病,在活产婴儿中发病率约为1/10,000-1/20,000。它是由于染色体7q11.23微缺失而导致的一种邻接基因缺失综合征,最常见的缺失片段大小为1.55Mb。该病多为散发,部分为常染色体显性遗传。在基因检测方面,本课题自行设计并建立了MLPA技术平台,成功对五例临床疑似WBS患者进行了基因分析,并最终确诊。其中一例为父源缺失,其余四例均为母源缺失。在结果的验证过程中发现,WBS缺失关键区域的短串联重复序列(short tandem repeat, STR)在家系分析时总能提供丰富的多态性信息。因此,本课题首次对这些STR位点在小样本中进行了多态性的初步分析,为优选DNA标记位点进行WBS的缺失检测提供了一定的理论依据。在以后的WBS检测中可首选本研究总结出的STR位点进行分析,将获得较高的阳性检出率。对于阴性者再考虑如MLPA等的其他技术进行检测。
先天性眼球震颤(Congenital nystagmus, CN)是一种遗传性眼病,具有遗传异质性，已知的有X连锁显性遗传、X连锁隐性遗传(MIM 310700)、常染色体显性遗传(MIM 164100,MIM 608345,MIM 193003)、常染色体隐性遗传(MIM 257400)这四种遗传方式,而X连锁遗传(伴外显不全和表型变异)方式是最常见的。
目前,共发现了3个X连锁位点,分别定位于Xp22,Xp11.3-11.4,和Xq26-Xq27。位于Xq26-27的FRMD7 (FERM domain-containing 7, MIM 300628)基因和位于Xp22的G蛋白偶联受体143(G protein-coupled receptor 143, GPR143, MIM 300500)基因是两个已发现的X连锁先天性眼球震颤(X-linked congenital nystagmus, XLCN)的致病基因,其中,GPR143基因突变亦导致眼白化病1型(ocular albinism type 1, OA1)的发生。目前,在两个XLCN的中国家系中均发现了GPR143基因突变。
本研究样本是一个四代的XLCN中国家系。所有受累患者均表现有眼球震颤和弱视,无典型的视网膜色素减退。经等位共享分析,致病基因与Xp22.3连锁,后直接测序发现了一例新的GPR143基因序列改变：c.291_309dup。我们认为这一改变很可能是这一XLCN家系的致病突变。
Multiplex ligation-dependent probe amplification (MLPA) is a recently developed relative semi-quantitative technology. The procedure contains hybridization, ligation, PCR amplification and electrophoretic separation, by which copy number varations of up to 45 different nucleotide sequences can be detected in a single reaction simultaneously. It has been used successfully in clinical diagnosis such as Duchenne muscular dystrophy (DMD), mental retardation and kinds of syndromes caused by microdeletions or microduplications. In this study, MLPA was introducted to detect copy number variations in patients with DMD and Williams-Beuren syndrome (WBS). Based on the results and evaluation of the new method, more available and appropriate molecular diagnostic strategy for Chinese DMD/WBS patients was set up successfully, which will be popularized much easier among basic units.
DMD is an X-linked recessive fatal disorder. It's the most common form of hereditary muscular dystrophy, with an incidence of about 1/3500 male births. Progressive proximal muscular dystrophy, powerless and characteristic pseudohypertrophy of the calves, caused by abnormal expression of dystrophin protein in the tissue of striped muscle is the most common clinical manifestations. The gene, DMD, was mapped to chromosome Xp21.1-21.3, which consists of 79 exons and spans more than 2.3 Mb. Exon deletions, duplications and other micro changes as point mutation are molecular defects underlying the disease. One hundred and sixteen DMD patients were detected by MLPA in the present study and the spectrum of deletion mutations in Chinese DMD patients was indicated by analysis of 380 deletion cases. A new multiplex PCR (mPCR) system'5×2+6'was established based on this analysis. In common units, especially grass-roots departments, it can be a preferred option for genetic analysis of DMD and MLPA as a supplement method. Co-application of mPCR and MLPA is to improve the molecular diagnostic strategy of Chinese DMD patients, making it more simple, rapid and efficient.
Williams-Beuren syndrome is a rare genetic disorder (1/10,000-20,000 in live births) caused by a heterozygous deletion on chromosome 7q11.23. Common deletions in WBS patients span a genomic region of 1.55Mb. The disease is generally sporadic although rare familial cases of autosomal dominant transmission have been reported. In this study, five WBS patients were diagnosed by our homemade MLPA method. One was deletion of paternal, the rest four were deletions of maternal. When testing the MLPA results, we found that short tandem repeats (STR) within the critical deletion region of WBS were always of high informative. Then polymorphism analysis of these STRs was performed on normal controls for the first time interiorly, which provides a theoretical basis for optimizing DNA markers when detecting deletions in Chinese WBS patients. Therefore, genetic analysis can be performed firstly using STR sites picked up in this study, which will receive a much higher positive rate.
Congenital nystagmus (CN) is an ocular hereditary disorder characterized by binocular spontaneous oscillations that is present at birth or develops within the first few months of life. So far, X-linked dominant and X-linked recessive (MIM 310700), autosomal dominant (MIM 164100, MIM 608345, MIM 193003), and autosomal recessive (MIM 257400) modes of inheritance have been reported, but X-linked inheritance with incomplete penetrance and variable expressivity is probably the most common. Three different genetic loci for X-linked congenital nystagmus (XLCN) have been mapped to chromosomes Xp11.3-11.4, Xp22 and Xq26-Xq27.
The FERM domain-containing 7 (FRMD7, MIM 300628) gene located at Xq26-27 and the G protein-coupled receptor 143 (GPR143, MIM 300500) gene at Xp22, have been identified as disease-causing genes for XLCN, but the etiology or molecular pathogenic mechanism is largely unknown. To date, multiple mutations of FRMD7 have been reported. Another gene, GPR143, also known as the OA1 gene, causes ocular albinism type 1 (OA1). However, GPR143 gene mutations have been identified in two Chinese families with XLCN without any classical phenotype of OA1 but only with congenital nystagmus.
In this study, we present a four generation Chinese family with XLCN. All the affected individuals suffer from nystagmus but without any typical sign of OA1. We mapped the disease-causing gene to Xp22.3 and characterised the underlying molecular defect as a novel 19-bp duplication in exon 1 of GPR143, causing a frame-shift in all affected males. Our results indicate that this novel GPR143 mutation might cause the XLCN in this Chinese family.
一、Duchenne肌营养不良症
DMD是一种人类常见的致死性X连锁隐性遗传的神经肌肉系统疾病,发病率约为活产男婴的1/3500,约1/3是散发病例。由于抗肌萎缩蛋白基因突变影响dystrophin蛋白在横纹肌组织的表达,导致肢体近端骨骼肌进行性萎缩、无力和腓肠肌假性肥大。致病基因DMD位于Xp21.1-21.3,含79个外显子。该病发生的分子基础包括基因的部分缺失、部分重复及点突变等微小改变。本文首先对116例DMD患者的MLPA结果进行了分析评价,并在统计分析前期380例DMD患者的基因缺失突变谱的基础上,建立了更适合于中国人DMD基因突变检测的多重PCR新体系“5×2+6”,在普通单位尤其是基层,它可作为DMD基因检测的首选方案,而MLPA技术作为补充。两者的联合应用旨在建立更加简便、快速、高效的DMD分子诊断策略。此外,本文亦对中国地区DMD患者的基因缺失/重复突变特点进行了详细而深入的总结探讨。
二、威廉斯综合征
威廉斯综合征是一种少见的遗传性精神发育迟滞性疾病,在活产婴儿中发病率约为1/10,000-1/20,000。它是由于染色体7q11.23微缺失而导致的一种邻接基因缺失综合征,最常见的缺失片段大小为1.55Mb。该病多为散发,部分为常染色体显性遗传。在基因检测方面,本课题自行设计并建立了MLPA技术平台,成功对五例临床疑似WBS患者进行了基因分析,并最终确诊。其中一例为父源缺失,其余四例均为母源缺失。在结果的验证过程中发现,WBS缺失关键区域的短串联重复序列(short tandem repeat, STR)在家系分析时总能提供丰富的多态性信息。因此,本课题首次对这些STR位点在小样本中进行了多态性的初步分析,为优选DNA标记位点进行WBS的缺失检测提供了一定的理论依据。在以后的WBS检测中可首选本研究总结出的STR位点进行分析,将获得较高的阳性检出率。对于阴性者再考虑如MLPA等的其他技术进行检测。
先天性眼球震颤(Congenital nystagmus, CN)是一种遗传性眼病,具有遗传异质性，已知的有X连锁显性遗传、X连锁隐性遗传(MIM 310700)、常染色体显性遗传(MIM 164100,MIM 608345,MIM 193003)、常染色体隐性遗传(MIM 257400)这四种遗传方式,而X连锁遗传(伴外显不全和表型变异)方式是最常见的。
目前,共发现了3个X连锁位点,分别定位于Xp22,Xp11.3-11.4,和Xq26-Xq27。位于Xq26-27的FRMD7 (FERM domain-containing 7, MIM 300628)基因和位于Xp22的G蛋白偶联受体143(G protein-coupled receptor 143, GPR143, MIM 300500)基因是两个已发现的X连锁先天性眼球震颤(X-linked congenital nystagmus, XLCN)的致病基因,其中,GPR143基因突变亦导致眼白化病1型(ocular albinism type 1, OA1)的发生。目前,在两个XLCN的中国家系中均发现了GPR143基因突变。
本研究样本是一个四代的XLCN中国家系。所有受累患者均表现有眼球震颤和弱视,无典型的视网膜色素减退。经等位共享分析,致病基因与Xp22.3连锁,后直接测序发现了一例新的GPR143基因序列改变：c.291_309dup。我们认为这一改变很可能是这一XLCN家系的致病突变。
Multiplex ligation-dependent probe amplification (MLPA) is a recently developed relative semi-quantitative technology. The procedure contains hybridization, ligation, PCR amplification and electrophoretic separation, by which copy number varations of up to 45 different nucleotide sequences can be detected in a single reaction simultaneously. It has been used successfully in clinical diagnosis such as Duchenne muscular dystrophy (DMD), mental retardation and kinds of syndromes caused by microdeletions or microduplications. In this study, MLPA was introducted to detect copy number variations in patients with DMD and Williams-Beuren syndrome (WBS). Based on the results and evaluation of the new method, more available and appropriate molecular diagnostic strategy for Chinese DMD/WBS patients was set up successfully, which will be popularized much easier among basic units.
DMD is an X-linked recessive fatal disorder. It's the most common form of hereditary muscular dystrophy, with an incidence of about 1/3500 male births. Progressive proximal muscular dystrophy, powerless and characteristic pseudohypertrophy of the calves, caused by abnormal expression of dystrophin protein in the tissue of striped muscle is the most common clinical manifestations. The gene, DMD, was mapped to chromosome Xp21.1-21.3, which consists of 79 exons and spans more than 2.3 Mb. Exon deletions, duplications and other micro changes as point mutation are molecular defects underlying the disease. One hundred and sixteen DMD patients were detected by MLPA in the present study and the spectrum of deletion mutations in Chinese DMD patients was indicated by analysis of 380 deletion cases. A new multiplex PCR (mPCR) system'5×2+6'was established based on this analysis. In common units, especially grass-roots departments, it can be a preferred option for genetic analysis of DMD and MLPA as a supplement method. Co-application of mPCR and MLPA is to improve the molecular diagnostic strategy of Chinese DMD patients, making it more simple, rapid and efficient.
Williams-Beuren syndrome is a rare genetic disorder (1/10,000-20,000 in live births) caused by a heterozygous deletion on chromosome 7q11.23. Common deletions in WBS patients span a genomic region of 1.55Mb. The disease is generally sporadic although rare familial cases of autosomal dominant transmission have been reported. In this study, five WBS patients were diagnosed by our homemade MLPA method. One was deletion of paternal, the rest four were deletions of maternal. When testing the MLPA results, we found that short tandem repeats (STR) within the critical deletion region of WBS were always of high informative. Then polymorphism analysis of these STRs was performed on normal controls for the first time interiorly, which provides a theoretical basis for optimizing DNA markers when detecting deletions in Chinese WBS patients. Therefore, genetic analysis can be performed firstly using STR sites picked up in this study, which will receive a much higher positive rate.
Congenital nystagmus (CN) is an ocular hereditary disorder characterized by binocular spontaneous oscillations that is present at birth or develops within the first few months of life. So far, X-linked dominant and X-linked recessive (MIM 310700), autosomal dominant (MIM 164100, MIM 608345, MIM 193003), and autosomal recessive (MIM 257400) modes of inheritance have been reported, but X-linked inheritance with incomplete penetrance and variable expressivity is probably the most common. Three different genetic loci for X-linked congenital nystagmus (XLCN) have been mapped to chromosomes Xp11.3-11.4, Xp22 and Xq26-Xq27.
The FERM domain-containing 7 (FRMD7, MIM 300628) gene located at Xq26-27 and the G protein-coupled receptor 143 (GPR143, MIM 300500) gene at Xp22, have been identified as disease-causing genes for XLCN, but the etiology or molecular pathogenic mechanism is largely unknown. To date, multiple mutations of FRMD7 have been reported. Another gene, GPR143, also known as the OA1 gene, causes ocular albinism type 1 (OA1). However, GPR143 gene mutations have been identified in two Chinese families with XLCN without any classical phenotype of OA1 but only with congenital nystagmus.
In this study, we present a four generation Chinese family with XLCN. All the affected individuals suffer from nystagmus but without any typical sign of OA1. We mapped the disease-causing gene to Xp22.3 and characterised the underlying molecular defect as a novel 19-bp duplication in exon 1 of GPR143, causing a frame-shift in all affected males. Our results indicate that this novel GPR143 mutation might cause the XLCN in this Chinese family.
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