一例NPHP1纯合缺失所致的Joubert综合征
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摘要
患儿,男,因"6月龄竖头欠稳"于浙江大学医学院附属儿童医院康复科就诊。查体发现双眼追视欠灵活,竖头欠稳,不会翻身,双手握拳,双下肢负重差,四肢肌张力低。磁共振结果显示小脑蚓部小,中脑呈"磨牙状"改变,诊断为Joubert综合征。全外显子组测序及Sanger测序发现患儿存在AHI1基因的杂合移码突变(c.533_534delAA),该突变位点遗传自母亲;而针对已知致病基因的拷贝数变异分析提示NPHP1基因可能存在纯合型缺失。经多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)方法进行验证,结果表明患儿的NPHP1基因确实存在纯合型缺失,且父母均为NPHP1杂合缺失的携带者。这是国内首次报道的由NPHP1纯合缺失所导致的Joubert综合征病例。由于NPHP1基因突变与肾脏损害相关性较高,应注意对此类突变患儿的密切随访。
A male patient at 6 months was admitted to the Rehabilitation Department,the Children' s Hospital,School of Medicine,Zhejiang University due to "vertical head instability".Physical examination found that hypotonia and ocular motor apraxia,the vertical head instable,the body could not turn over,the hands clenched fists,the lower limbs were poor in weight bearing,and the muscle tension of the limbs was low.Magnetic resonance results showed the cerebellar vermis hypoplasia and midbrain "molar tooth sign",diagnosed as Joubert syndrome.Whole exome sequencing(WES)and Sanger sequencing was applied to examine the DNA sample of the proband.A heterozygous frameshift variant of AHI1,c.533_534 delAA was found in proband,which was inherited from his mother.In addition,a homozygous deletion of the whole NPHP1 gene was suggested by the WES and eventually confirmed by multiplex ligation-dependent probe amplification(MLPA)detection of both the proband and his parents.Both the parents were the carriers of NPHP1 heterozygous deletion.This is the first case of Chinese Joubert syndrome caused by homozygous deletion of NPHP1.Follow-up should be necessary due to the high risk of renal involvement of NPHP1 deletion.
A male patient at 6 months was admitted to the Rehabilitation Department,the Children' s Hospital,School of Medicine,Zhejiang University due to "vertical head instability".Physical examination found that hypotonia and ocular motor apraxia,the vertical head instable,the body could not turn over,the hands clenched fists,the lower limbs were poor in weight bearing,and the muscle tension of the limbs was low.Magnetic resonance results showed the cerebellar vermis hypoplasia and midbrain "molar tooth sign",diagnosed as Joubert syndrome.Whole exome sequencing(WES)and Sanger sequencing was applied to examine the DNA sample of the proband.A heterozygous frameshift variant of AHI1,c.533_534 delAA was found in proband,which was inherited from his mother.In addition,a homozygous deletion of the whole NPHP1 gene was suggested by the WES and eventually confirmed by multiplex ligation-dependent probe amplification(MLPA)detection of both the proband and his parents.Both the parents were the carriers of NPHP1 heterozygous deletion.This is the first case of Chinese Joubert syndrome caused by homozygous deletion of NPHP1.Follow-up should be necessary due to the high risk of renal involvement of NPHP1 deletion.
引文
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[18]Chaki M,Hoefele J,Allen SJ,et al.Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies[J].Kidney Int,2011,80:1239-1245.
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[23]Wang L,Yang Y,Song J,et al.Two novel mutations in the C-terminal region of centrosomal protein 290(CEP290)result in classic Joubert syndrome[J].J Child Neurol,2015,30:772-776.
[24]张蔓丽,周红辉,卢彦平,等.目标外显子捕获技术在初级纤毛相关疾病基因检测中的应用[J].中华围产医学杂志,2016,19:422-426.
[25]孟晨,张开慧,马静,等.OFD1基因突变引起的+Joubert+综合征10型一例临床和基因分析[J].中华儿科杂志,2017,55:131-134.
[26]罗敏娜,曹宗富,陈军,等.全外显子组测序发现中国Joubert综合征家系C5orf42基因的新突变[J].生殖医学杂志,2017,26:464-469.
[27]罗敏娜,刘志翠,曹宗富,等.全外显子组测序发现CSPP1所致Joubert综合征1例[J].中国计划生育学杂志,2018,26:56-61.
[28]罗敏娜,刘志敏,沈玥,等.目标外显子组捕获测序发现INPP5E突变致Joubert综合征1例.[J].中国计划生育学杂志,2018,26:400-404.
[29]陈芳,孙素真,唐洪侠,等.INPP5E基因变异所致Joubert综合征一家系报道[J].中国当代儿科杂志,2018,20:861-863.
[30]余明惠,沈茜.肾单位肾痨致病基因相关信号通路研究进展[J].国际儿科学杂志,2018,45:1-4.
[31]孙良忠,林宏容,岳智慧,等.少年型肾单位肾痨13例临床特点和基因突变分析[J].中华儿科杂志,2016,54:834-839.
[32]孙良忠.肾单位肾痨临床表型与基因突变研究进展[J].广东医学,2015,36:1965-1967.
[33]管娜,张宏文,丁洁,等.家族性少年型肾单位肾痨的临床和基因诊断[J].临床儿科杂志,2008,26:287-290.
[34]Wodarczyk C,Distefano G,Rowe I,et al.Nephrocystin-1forms a complex with polycystin-1via a polyproline motif/SH3domain interaction and regulates the apoptotic response in mammals[J/OL].PLoS One,2010,5:e12719.
[2]黄山雅美,刘捷,曾超美.Joubert综合征[J].中华临床医师杂志(电子版),2017,11:1409-1413.
[3]Maria BL,Boltshauser E,Palmer SC,et al.Clinical features and revised diagnostic criteria in Joubert syndrome[J].JChild Neurol,1999,14:583-591.
[4]Maria BL,Quisling RG,Rosainz LC,et al.Molar tooth sign in Joubert syndrome:clinical,radiologic,and pathologic significance[J].J Child Neurol,1999,14:368-376.
[5]Ben-Salem S,Al-Shamsi AM,Gleeson JG,et al.Mutation spectrum of Joubert syndrome and related disorders among Arabs[J].Hum Genome Var,2014,1:14020.
[6]Bachmann-Gagescu R,Dempsey JC,Phelps IG,et al.Joubert syndrome:a model for untangling recessive disorders with extreme genetic heterogeneity[J].J Med Genet,2015,52:514-522.
[7]Kroes HY,Monroe GR,van der Zwaag B,et al.Joubert syndrome:genotyping a Northern European patient cohort[J].Eur J Hum Genet,2016,24:214-220.
[8]Vilboux T,Doherty DA,Glass IA,et al.Molecular genetic findings and clinical correlations in 100patients with Joubert syndrome and related disorders prospectively evaluated at a single center[J].Genet Med,2017,19:875-882.
[9]Hebbar M,Kanthi A,Shukla A et al.A biallelic 36-bp insertion in PIBF1is associated with Joubert syndrome[J].JHum Genet,2018,63:935-939.
[10]Saraiva J M,Baraitser M.Joubert syndrom:a review[J].Am J Med Genet 1992,43:726-731.
[11]Maria BL,Hoang KB,Tusa RJ,et al.“Joubert syndrome”revisited:key ocular motor signs with magnetic resonance imaging correlation[J].J Child Neurol,1997,12:423-430.
[12]Srour M,Hamdan FF,McKnight D,et al.Joubert syndrome in French Canadians and identification of mutations in CEP104[J].Am J Hum Genet,2015,97:744-753.
[13]Reiter JF,Leroux MR.Genes and molecular pathways underpinning ciliopathies[J].Nat Rev Mol Cell Biol,2017,18:533-547.
[14]Hildebrandt F,Otto E,Rensing C,et al.A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1[J].Nat Genet,1997,17:149-153.
[15]Parisi MA,Bennett CL,Eckert ML,et al.The NPHP1gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome[J].Am JHum Genet,2004,75:82-91.
[16]Fliegauf M,Horvath J,von Schnakenburg C,et al.Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia[J].J Am Soc Nephrol,2006,17:2424-2433.
[17]王少华,李媛媛,章友康,等.少年型肾单位肾痨Ⅰ型临床特点和基因诊断[J].中国中西医结合肾病杂志,2017,18:498-501.
[18]Chaki M,Hoefele J,Allen SJ,et al.Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies[J].Kidney Int,2011,80:1239-1245.
[19]Halbritter J,Porath JD,Diaz KA,et al.Identification of 99novel mutations in a worldwide cohort of 1,056patients with a nephronophthisis-related ciliopathy[J].Hum Genet,2013,132:865-884.
[20]苏艳华,谢建生,尉姗姗,等.CC2D2A基因变异所致Joubert综合征一家系的临床及分子遗传学分析[J].中华儿科杂志,2015,53:431-435.
[21]Chen Z,Wang JL,Tang BS,et al.Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders[J].Neurobiol Aging,2013,34:2442.e11-e17.
[22]陈曦,李胜利,文华轩,等.Joubert综合征及相关疾病的产前及产后影像学研究[J].中华医学超声杂志(电子版),2014,11:508-513.
[23]Wang L,Yang Y,Song J,et al.Two novel mutations in the C-terminal region of centrosomal protein 290(CEP290)result in classic Joubert syndrome[J].J Child Neurol,2015,30:772-776.
[24]张蔓丽,周红辉,卢彦平,等.目标外显子捕获技术在初级纤毛相关疾病基因检测中的应用[J].中华围产医学杂志,2016,19:422-426.
[25]孟晨,张开慧,马静,等.OFD1基因突变引起的+Joubert+综合征10型一例临床和基因分析[J].中华儿科杂志,2017,55:131-134.
[26]罗敏娜,曹宗富,陈军,等.全外显子组测序发现中国Joubert综合征家系C5orf42基因的新突变[J].生殖医学杂志,2017,26:464-469.
[27]罗敏娜,刘志翠,曹宗富,等.全外显子组测序发现CSPP1所致Joubert综合征1例[J].中国计划生育学杂志,2018,26:56-61.
[28]罗敏娜,刘志敏,沈玥,等.目标外显子组捕获测序发现INPP5E突变致Joubert综合征1例.[J].中国计划生育学杂志,2018,26:400-404.
[29]陈芳,孙素真,唐洪侠,等.INPP5E基因变异所致Joubert综合征一家系报道[J].中国当代儿科杂志,2018,20:861-863.
[30]余明惠,沈茜.肾单位肾痨致病基因相关信号通路研究进展[J].国际儿科学杂志,2018,45:1-4.
[31]孙良忠,林宏容,岳智慧,等.少年型肾单位肾痨13例临床特点和基因突变分析[J].中华儿科杂志,2016,54:834-839.
[32]孙良忠.肾单位肾痨临床表型与基因突变研究进展[J].广东医学,2015,36:1965-1967.
[33]管娜,张宏文,丁洁,等.家族性少年型肾单位肾痨的临床和基因诊断[J].临床儿科杂志,2008,26:287-290.
[34]Wodarczyk C,Distefano G,Rowe I,et al.Nephrocystin-1forms a complex with polycystin-1via a polyproline motif/SH3domain interaction and regulates the apoptotic response in mammals[J/OL].PLoS One,2010,5:e12719.