一例NPHP1纯合缺失所致的Joubert综合征  

A patient with Joubert syndrome caused by homozygous deletion of NPHP1

作　　者：马斯禹 阮雯聪[3] 曹宗富 李海峰[3] 沈玥 蔡瑞琨 陆超 罗敏娜 马旭 高华方 邹艳[5] MA Si-yu;RUAN Wen-cong;CAO Zong-fu;LI Hai-feng;SHEN Yue;CAI Rui-kun;LU Chao;LUO Min-na;MA Xu;GAO Hua-fang;ZOU Yan(Graduate School of Peking Union Medical College,Beijing 100730;National Research Institute for Family Planning,Beijing 100081;The Children ’s Hospital,School of Medicine,Zhejiang University,Hangzhou 310003;National Human Genetic Resources Center,Beijing 102206;Zhejiang Provincial Center for Disease Control and Prevention,Hangzhou 310051)

机构地区：[1]北京协和医学院研究生院,北京100730 [2]国家卫生健康委科学技术研究所,北京100081 [3]浙江大学医学院附属儿童医院,杭州310003 [4]国家人类遗传资源中心,北京102206 [5]浙江省疾病预防控制中心,杭州310051

出　　处：《生殖医学杂志》2019年第7期797-804,共8页Journal of Reproductive Medicine

基　　金：国家重点研发计划(2016YFC1000307);中央级公益性科研院所基本科研业务费专项(2018GJZ02)

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_534delAA 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.

关 键 词：JOUBERT综合征 NPHP1 全外显子组测序 小脑蚓部发育不良 肾单位肾痨 

分 类 号：R596.2[医药卫生—内科学]