甘肃省新生儿听力与聋病易感基因联合筛查的流行病学研究
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摘要
先天性听力损失是最常见的出生缺陷。据国外报道,正常新生儿的发病率为1‰～3‰；而我国各地报道的先天性听力损失发病率却存在差异,约介于1.01‰～9.52‰,其中70%患儿表现为孤立的听力障碍,属于非综合征型听力损失,不易早期发现。部分患儿表现为迟发性、进行性听力障碍,若不采取有效的早期诊断、早期干预、早期治疗等措施可能会与潜在的耳聋群体失之交臂,造成较大的家庭与社会负担。有研究表明50%的先天性耳聋患者是由遗传因素导致,25%的耳聋是由环境因素导致,其余25%耳聋病因不明。如何能实现先天性听力损失的“三早”预防,是全世界听力学工作者不断探索的动力与目标。近十余年来随着我国新生儿听力筛查工作的开展,其不足与缺陷逐渐暴露,耳聋病因学研究成为又一热点,推动了新生儿听力与聋病易感基因联合筛查的研究。甘肃省作为中国西北地区重要组成部分,具有地域广阔、民族众多、经济文化发展不平衡等特点,因此选作研究偏远的多民族聚集地区先天性听力损失发病情况及常见聋病易感基因突变频率的模型颇具合理性。本课题对2009年9月30日—2010年9月30日出生于该地区的96711例新生儿进行了听力筛查,并对其中2384例新生儿开展了聋病易感基因筛查。
第一部分甘肃省96711例新生儿普遍听力筛查结果分析
本研究采用畸变产物耳声发射对2009年9月30日—2010年9月30日出生于甘肃省76个县/区的96711例新生儿及婴幼儿在其出生后三月龄内实施普遍听力筛查,未通过者间隔一月进行复筛；仍未通过者进行听力学诊断检查及跟踪随访。研究期间出生于该地区的新生儿达247864例,其中接受听力筛查的新生儿及婴幼儿有96711例,该地区初筛覆盖率达39.02%。接受初筛的新生儿及婴幼儿中,通过者81758例,初筛通过率84.54%,未通过者14953例,未通过率15.46%。根据有无高危因素将研究对象分为正常儿组和高危儿组,卡方检验表明正常儿组初筛通过率显著高于高危儿组(x2=4.7926,P=-0.0286)。根据性别不同将研究对象分为男婴组和女婴组,卡方检验表明女婴组初筛通过率显著高于男婴组(x2=41.0967,P<.0001)。根据分娩方式不同将研究对象分为阴式分娩组和剖腹产组,卡方检验表明剖腹产组初筛通过率显著高于阴式分娩组(x=4.5827,P=0.0323)。对四个主要民族间两两比对卡方检验表明,汉族初筛通过率显著高于回族(x2=1095.0332,P<.0001),回族初筛通过率显著低于藏族(x2=157.9922,P<.0001)和东乡族(x2=7.0858,P=0.0078)。初筛未通过需进行复筛的14953例新生儿及婴幼儿中,实际接受复筛者4689例,复筛率达31.36%,复筛通过者4250例(90.64%),未通过者439例(9.36%)。开展新生儿听力筛查的76个县/区中,除了阿克塞县外临洮县初筛覆盖率最高。对甘肃省14个市/州初筛情况采用卡方检验后表明,各地区初筛通过率差异显著(x2=2042.218,P<.0001)；两两组间比较表明,除天水与酒泉、甘南与天水、武威与天水、甘南与酒泉、武威与甘南、武威与酒泉、酒泉与平凉、张掖与白银、张掖与金昌、白银与金昌之间差异不显著外,其它各地区之间差异显著。对甘肃省2个地区初筛情况采用卡方检验表明,河西地区初筛通过率显著高于河东地区(x2=121.7278,P<.0001)。因此,性别、民族、高危因素、分娩方式及地域差异均可影响初筛通过率。采用畸变产物耳声发射技术对农村及城乡结合地区广泛开展新生儿听力筛查是可行的,但目标人群初筛覆盖率、复筛率、转诊率低,漏筛率、失访率高仍是亟待解决的问题。
第二部分甘肃省河西走廊地区2384例新生儿聋病易感基因筛查结果分析
本研究通过对2009年11月——2010年4月出生于甘肃省河西走廊地区的2384例新生儿常见耳聋基因SLC26A4及mtDNA 12SrRNA m.1494及1555位点的检测、分析,发现30例携带SLC26A4 919-2A>G单等位基因突变,该位点总体突变频率为12.58‰,酒泉市、金昌市、张掖市、武威市各地区该位点突变频率分别为0‰,0‰,13.37‰,13.38‰。6例检测到mtDNA12rRNAm.1555A>G均质性突变,2例mtDNA12rRNAm.1555A>G异质性突变,未检测到mtDNA12rRNAm.1494C>T位点突变,此位点总体突变频率为3.36‰(包括均质性和异质性突变),酒泉市、金昌市、张掖市、武威市各地区该位点突变频率分别为0‰,0‰,2.81‰,4.87‰。本研究得出张掖市、武威市大前庭水管综合症相关的SLC26A4 919-2A>G位点突变频率相当,但氨基糖苷类抗生素致聋相关的mtDNA12rRNAm.1555A>G位点突变频率武威市远高于其他三个地区。
Congenital hearing loss is one of the most common birth defect. It's reported that the incidence of Congenital hearing loss is 1‰～3‰abroad. But in China the incidence varies from place to place, which is between 1.01‰～9.52‰. Seventy percent of patients have the manifestation of solitary dysaudia belonging to non-syndromic hearing impairment, which is hardly detected in early stage. Others presents with tardive or progressive dysaudia. In case we don't take effective measures such as early diagnosis, early intervention and early treatment, they will join in the potential deaf population, causing a greater burden on families and society. Previous Researches show that 50% of congenital deafness is caused by heredity,25% by environmental factors, the remaining 25% is not clear. Effective early prevention for patients with congenital hearing loss is the goal and drive for audiology researchers in the world. Along with the advance of newborn hearing screening in china for nearly ten more years, the warts and pimples are gradually exposed, the etiology of hearing loss becomes another research hot point, which promotes the project of newborn hearing combined with deafness gene genotyping in wider area in China. Gansu province is an important part of northwest of China with the features of broad area, different nationalities and unblanced economic development. It could be a classic documentation for the epidemiologic study on new born hearing combined with deafness gene genotyping in rural area. In this study 96711 infants who were born in Gansu province from September 30th 2009 to September 30th 2010 received universal newborn hearing initial screening, and concerned deafness genes were genotyped in 2384 infants.
Part 1 Analysis on 96711 cases of newborn hearing screening in Gansu province
Ninety-six thousand seven hundred and eleven infants who were born in 76 counties or districts of Gansu province from September 30th 2009 to September 30th 2010 received universal newborn hearing initial screening using distortion product otoacoustic emission (DPOAE) before the age of three months. The infants who failed initial screening were checked again one month later. Follow-up and relevant assessments of the hearing were provided continually for those who failed both tests. Results show that about 247864 infants were born in this period, of which 96711 received newborn hearing initial screening, the coverage rate is 39.02%. Among 96711 infants, 81758 (84.54%) infants passed the initial test and 14953 (15.46%) failed. All infants were divided into two groups by high risk factors:N group(without high risk factors, normal newborn) and H group(with high risk factors). Chi-square tests show in the initial screening the pass rate of N group is significantly higher than the H group (χ2=4.7926, P=0.0286). When considering the gender, we found that in the initial screening the pass rate of female group is significantly higher than male group (χ2=41.0967, P<.0001). When the infants were divided into two groups by different delivery modes, we found in the initial screening the pass rate of cesarean section group is significantly higher than nature delivery group (χ2=4.5827, P=0.0323). Pairwise comparison by the chi-square tests of the initial screening pass rate among the four main peoples Han, Hui, Zang and Dongxiang, results show that Han is significantly higher than Hui(χ2=1095.0332, P <.0001), Hui is significantly lower than Zang(χ2=157.9922, P<.0001) and Dongxiang(χ2=7.0858, P=0.0078). Fourteen thousand nine hundred and fifty-three infants needed rescreening, however only 4689(31.36%) accepted rescreening on time, of which 4250(90.64%) passed and 439 (9.36%) failed. In the 76 counties or districts, Akesai and Lintao counties have the highest coverage rate. Chi-square tests show the pass rate is significantly different between the fourteen cities (χ2=2042.218, P<.0001). Pairwise comparison shows Tianshui and Jiuquan, Gannan and Tianshui, Wuwei and Tianshui, Gannan and Jiuquan, Wuwei and Gannan, Wuwei and Jiuquan, Jiuquan and Pingliang, Zhangye and Baiyin, Zhangye and Jinchang, Baiyin and Jinchang were not significantly different, other pairs were significantly different. Chi-square tests show the pass rate of Hexi district is significantly higher than Hedong district (χ2=121.7278,P<.0001).From the results above, we can make a conclusion that gender, people, high risk factors, delivery modes and geographical variation influence the pass rate of newborn hearing initial screening. In all, it is feasible to conduct universal hearing screening program in the rural areas using distortion product otoacoustic emission (DPOAE), however, the suitable model to perform the program is urgently needed to be set up in order to improve the accuracy and widen the scope of screening.
Part 2 Deafness Genes Screening on 2384 newborns in Gansu corridor area
In this study, SLC26A4, mtDNA 12SrRNA m.1494 and mtDNA 12SrRNA m.1555 were genotyped in 2384 infants who were born in Gansu corridor area from November 2009 to April 2010. Results show that 30 patients were detected with SLC26A4 919-2A>G monoallelic mutations, total mutations frequency is 12.58%o, while in Jiuquan city, Jinchang city, Zhangye city, Wuwei city the frequency is 0‰,0‰,13.37‰,13.38‰, respectively. Six patients were detected with mtDNA12rRNAm.1555A>G homogeneity mutation,2 patients were detected with mtDNA12rRNAm.1555A>G heterogeneity mutation, mtDNA12rRNAm.1494C>T were not detected in this population, total mutations frequency is 3.36%o(including homogeneity and heterogeneity mutation), while in Jiuquan city, Jinchang city, Zhangye city, Wuwei city the frequency is 0‰,0‰,2.81‰,4.87‰, respectively. In conclusion, the mutation frequency of SLC26A4 919-2A>G in relation to Large vestibular aqueduct syndrome is similar in Zhangye city and Wuwei city, but the frequency of mtDNA12rRNAm.1555A>G in relation to aminoglycoside antibiotic induced deafness in Wuwei city is far higher than other three cities.
第一部分甘肃省96711例新生儿普遍听力筛查结果分析
本研究采用畸变产物耳声发射对2009年9月30日—2010年9月30日出生于甘肃省76个县/区的96711例新生儿及婴幼儿在其出生后三月龄内实施普遍听力筛查,未通过者间隔一月进行复筛；仍未通过者进行听力学诊断检查及跟踪随访。研究期间出生于该地区的新生儿达247864例,其中接受听力筛查的新生儿及婴幼儿有96711例,该地区初筛覆盖率达39.02%。接受初筛的新生儿及婴幼儿中,通过者81758例,初筛通过率84.54%,未通过者14953例,未通过率15.46%。根据有无高危因素将研究对象分为正常儿组和高危儿组,卡方检验表明正常儿组初筛通过率显著高于高危儿组(x2=4.7926,P=-0.0286)。根据性别不同将研究对象分为男婴组和女婴组,卡方检验表明女婴组初筛通过率显著高于男婴组(x2=41.0967,P<.0001)。根据分娩方式不同将研究对象分为阴式分娩组和剖腹产组,卡方检验表明剖腹产组初筛通过率显著高于阴式分娩组(x=4.5827,P=0.0323)。对四个主要民族间两两比对卡方检验表明,汉族初筛通过率显著高于回族(x2=1095.0332,P<.0001),回族初筛通过率显著低于藏族(x2=157.9922,P<.0001)和东乡族(x2=7.0858,P=0.0078)。初筛未通过需进行复筛的14953例新生儿及婴幼儿中,实际接受复筛者4689例,复筛率达31.36%,复筛通过者4250例(90.64%),未通过者439例(9.36%)。开展新生儿听力筛查的76个县/区中,除了阿克塞县外临洮县初筛覆盖率最高。对甘肃省14个市/州初筛情况采用卡方检验后表明,各地区初筛通过率差异显著(x2=2042.218,P<.0001)；两两组间比较表明,除天水与酒泉、甘南与天水、武威与天水、甘南与酒泉、武威与甘南、武威与酒泉、酒泉与平凉、张掖与白银、张掖与金昌、白银与金昌之间差异不显著外,其它各地区之间差异显著。对甘肃省2个地区初筛情况采用卡方检验表明,河西地区初筛通过率显著高于河东地区(x2=121.7278,P<.0001)。因此,性别、民族、高危因素、分娩方式及地域差异均可影响初筛通过率。采用畸变产物耳声发射技术对农村及城乡结合地区广泛开展新生儿听力筛查是可行的,但目标人群初筛覆盖率、复筛率、转诊率低,漏筛率、失访率高仍是亟待解决的问题。
第二部分甘肃省河西走廊地区2384例新生儿聋病易感基因筛查结果分析
本研究通过对2009年11月——2010年4月出生于甘肃省河西走廊地区的2384例新生儿常见耳聋基因SLC26A4及mtDNA 12SrRNA m.1494及1555位点的检测、分析,发现30例携带SLC26A4 919-2A>G单等位基因突变,该位点总体突变频率为12.58‰,酒泉市、金昌市、张掖市、武威市各地区该位点突变频率分别为0‰,0‰,13.37‰,13.38‰。6例检测到mtDNA12rRNAm.1555A>G均质性突变,2例mtDNA12rRNAm.1555A>G异质性突变,未检测到mtDNA12rRNAm.1494C>T位点突变,此位点总体突变频率为3.36‰(包括均质性和异质性突变),酒泉市、金昌市、张掖市、武威市各地区该位点突变频率分别为0‰,0‰,2.81‰,4.87‰。本研究得出张掖市、武威市大前庭水管综合症相关的SLC26A4 919-2A>G位点突变频率相当,但氨基糖苷类抗生素致聋相关的mtDNA12rRNAm.1555A>G位点突变频率武威市远高于其他三个地区。
Congenital hearing loss is one of the most common birth defect. It's reported that the incidence of Congenital hearing loss is 1‰～3‰abroad. But in China the incidence varies from place to place, which is between 1.01‰～9.52‰. Seventy percent of patients have the manifestation of solitary dysaudia belonging to non-syndromic hearing impairment, which is hardly detected in early stage. Others presents with tardive or progressive dysaudia. In case we don't take effective measures such as early diagnosis, early intervention and early treatment, they will join in the potential deaf population, causing a greater burden on families and society. Previous Researches show that 50% of congenital deafness is caused by heredity,25% by environmental factors, the remaining 25% is not clear. Effective early prevention for patients with congenital hearing loss is the goal and drive for audiology researchers in the world. Along with the advance of newborn hearing screening in china for nearly ten more years, the warts and pimples are gradually exposed, the etiology of hearing loss becomes another research hot point, which promotes the project of newborn hearing combined with deafness gene genotyping in wider area in China. Gansu province is an important part of northwest of China with the features of broad area, different nationalities and unblanced economic development. It could be a classic documentation for the epidemiologic study on new born hearing combined with deafness gene genotyping in rural area. In this study 96711 infants who were born in Gansu province from September 30th 2009 to September 30th 2010 received universal newborn hearing initial screening, and concerned deafness genes were genotyped in 2384 infants.
Part 1 Analysis on 96711 cases of newborn hearing screening in Gansu province
Ninety-six thousand seven hundred and eleven infants who were born in 76 counties or districts of Gansu province from September 30th 2009 to September 30th 2010 received universal newborn hearing initial screening using distortion product otoacoustic emission (DPOAE) before the age of three months. The infants who failed initial screening were checked again one month later. Follow-up and relevant assessments of the hearing were provided continually for those who failed both tests. Results show that about 247864 infants were born in this period, of which 96711 received newborn hearing initial screening, the coverage rate is 39.02%. Among 96711 infants, 81758 (84.54%) infants passed the initial test and 14953 (15.46%) failed. All infants were divided into two groups by high risk factors:N group(without high risk factors, normal newborn) and H group(with high risk factors). Chi-square tests show in the initial screening the pass rate of N group is significantly higher than the H group (χ2=4.7926, P=0.0286). When considering the gender, we found that in the initial screening the pass rate of female group is significantly higher than male group (χ2=41.0967, P<.0001). When the infants were divided into two groups by different delivery modes, we found in the initial screening the pass rate of cesarean section group is significantly higher than nature delivery group (χ2=4.5827, P=0.0323). Pairwise comparison by the chi-square tests of the initial screening pass rate among the four main peoples Han, Hui, Zang and Dongxiang, results show that Han is significantly higher than Hui(χ2=1095.0332, P <.0001), Hui is significantly lower than Zang(χ2=157.9922, P<.0001) and Dongxiang(χ2=7.0858, P=0.0078). Fourteen thousand nine hundred and fifty-three infants needed rescreening, however only 4689(31.36%) accepted rescreening on time, of which 4250(90.64%) passed and 439 (9.36%) failed. In the 76 counties or districts, Akesai and Lintao counties have the highest coverage rate. Chi-square tests show the pass rate is significantly different between the fourteen cities (χ2=2042.218, P<.0001). Pairwise comparison shows Tianshui and Jiuquan, Gannan and Tianshui, Wuwei and Tianshui, Gannan and Jiuquan, Wuwei and Gannan, Wuwei and Jiuquan, Jiuquan and Pingliang, Zhangye and Baiyin, Zhangye and Jinchang, Baiyin and Jinchang were not significantly different, other pairs were significantly different. Chi-square tests show the pass rate of Hexi district is significantly higher than Hedong district (χ2=121.7278,P<.0001).From the results above, we can make a conclusion that gender, people, high risk factors, delivery modes and geographical variation influence the pass rate of newborn hearing initial screening. In all, it is feasible to conduct universal hearing screening program in the rural areas using distortion product otoacoustic emission (DPOAE), however, the suitable model to perform the program is urgently needed to be set up in order to improve the accuracy and widen the scope of screening.
Part 2 Deafness Genes Screening on 2384 newborns in Gansu corridor area
In this study, SLC26A4, mtDNA 12SrRNA m.1494 and mtDNA 12SrRNA m.1555 were genotyped in 2384 infants who were born in Gansu corridor area from November 2009 to April 2010. Results show that 30 patients were detected with SLC26A4 919-2A>G monoallelic mutations, total mutations frequency is 12.58%o, while in Jiuquan city, Jinchang city, Zhangye city, Wuwei city the frequency is 0‰,0‰,13.37‰,13.38‰, respectively. Six patients were detected with mtDNA12rRNAm.1555A>G homogeneity mutation,2 patients were detected with mtDNA12rRNAm.1555A>G heterogeneity mutation, mtDNA12rRNAm.1494C>T were not detected in this population, total mutations frequency is 3.36%o(including homogeneity and heterogeneity mutation), while in Jiuquan city, Jinchang city, Zhangye city, Wuwei city the frequency is 0‰,0‰,2.81‰,4.87‰, respectively. In conclusion, the mutation frequency of SLC26A4 919-2A>G in relation to Large vestibular aqueduct syndrome is similar in Zhangye city and Wuwei city, but the frequency of mtDNA12rRNAm.1555A>G in relation to aminoglycoside antibiotic induced deafness in Wuwei city is far higher than other three cities.
引文
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[42]王文敏王彩,新生儿听力筛查最佳时间和方法[J].中国妇幼保健.2009(09)：1238-1240.
[43]黄丽辉,对新生儿听力筛查假阳性与假阴性的再认识[J]听力学及言语疾病杂志.2010(05)：413-414.
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[45]Everett L.A., Glaser B., Beck J.C., et al., Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)[J]. Nat Genet.1997,17(4):411-22.
[46]Bidart J.M., Mian C, Lazar V., et al., Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues[J]. J Clin Endocrinol Metab.2000,85(5):2028-33.
[47]Usami S., Abe S., Weston M.D., et al., Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations[J]. Hum Genet.1999,104(2):188-92.
[48]Li X.C., Everett L.A., Lalwani A.K., et al., A mutation in PDS causes non-syndromic recessive deafness[J]. Nat Genet.1998,18(3):215-7.
[49]赵亚丽,王秋菊,李庆忠,et al.,95例前庭水管扩大核心家系Slc26a4基因特异突变图谱[J].听力学及言语疾病杂志.2008(03).
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[54]李丽,何健,郭玉芬,et al.,1234例新生儿听力与聋病易感基因联合筛查[J].中国耳鼻咽喉头颈外科.2009(04)：187-189.
[55]Mafong D.D., Shin E.J., Lalwani A.K., Use of laboratory evaluation and radiologic imaging in the diagnostic evaluation of children with sensorineural hearing loss[J]. Laryngoscope.2002, 112(1):1-7.
[56]Griffith A.J., Arts A., Downs C., et al., Familial large vestibular aqueduct syndrome[J]. Laryngoscope.1996,106(8):960-5.
[57]Li Z.Y., Li R.H., Chen J.F., et al., Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss[J]. Human Genetics.2005,117(1):9-15.
[58]Guan M.X., Fischel-Ghodsian N., Attardi G., A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity[J]. Hum Mol Genet.2000,9(12):1787-93.
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[61]Estivill X., Govea N., Barcelo A., et al., Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides[J]. The American Journal of Human Genetics.1998,62(1):27-35.
[62]Price K.E., AMINOGLYCOSIDE RESEARCH 1975-1985 - PROSPECTS FOR DEVELOPMENT OF IMPROVED AGENTS[J]. Antimicrobial Agents and Chemotherapy. 1986,29(4):543-548.
[63]Zhu Q., Liu X., Han D., et al., [Molecular etiology of 573 patients with nonsyndromic hearing loss in 5 provinces of northwest region of China] [J]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi.2007,21(10):460-2.
[64]赵亚茹宋亮亮,新生儿听力筛查与耳聋的基因诊断[J].实用儿科临床杂志.2010(11)：790-791.