Front Genet:中国首例由SMPD4基因变异致NEDMABA的病例分析

2022-08-07 测序中国 测序中国

这项研究通过全外显子靶向捕获测序首次在中国报道了NEDMABA表型的病例,并为探究SMPD4在该综合征中的作用提供了进一步的临床与分子证据。

 SMPD4基因编码鞘磷脂磷酸二酯酶4,是一种优先水解鞘磷脂的酶。SMPD4的功能缺失变异已经被证实会导致伴有小头畸形、关节畸形和脑结构异常的一类神经发育障碍(NEDMABA)。南通市妇幼保健院医学遗传与产前诊断科王学谦博士团队,使用IDT 埃德特公司的xGen杂交捕获系统的Exome Research Panel对家系三人进行了全外显子组靶向捕获测序,首次在中国人群中检测到了NEDMABA相关的SMPD4新致病变异位点及跨全基因范围的CNV缺失,证实了SMPD4功能缺失是NEDMABA发生的遗传病因,该研究成果进一步拓展了我们对这一疾病遗传突变频谱的认知。

疾病简介

神经发育障碍(Neurodevelopmental disorders)是一类以患者无法发育达到认知、情绪及运动的里程碑为主要症状的疾病。这类疾病的病因非常复杂,有着极高的异质性,既可能由综合征、代谢异常、免疫紊乱等遗传因素导致,也可能与感染、身体创伤或接触有毒物质等环境因素相关。近期,有一种伴随有小头畸形、关节畸形和脑结构异常的神经发育障碍(Neurodevelopmental Disorder with Microcephaly, Arthrogryposis, and Structural Brain Anomalies, NEDMABA)被证实与水解鞘磷脂的SMPD4基因相关。

临床表现

该研究先证者为女性,是非近亲结婚的健康父母的第一个孩子,无明确家族史。超声显示,其在妊娠34+3周时即表现出胎儿生长受限(1695g,-2.7SD)且伴有小头畸形(274mm,-3.6SD)(如图1)。先证者在妊娠39+2 周出生,出生时体重为2,460克(-2.2 SD),新生儿0分钟和5分钟时的Apgar评分*均为9分。

*Apgar评分(Apgar Score)是一种对刚出生的新生婴儿健康状况快速评核方法,由五项指标组成,每个指标得分为0-2分,总分为0-10分。五个指标分别为:外观(Appearance),脉搏(Pulse),不快(Grimace),活动(Activity),呼吸(Respiration)。

图1. 34+3周胎儿的产前超声图像显示胎儿生长受限(A)

 且伴有小头畸形(B) 。

该先证者2个月时,因急性喘息性支气管炎、发育迟缓和癫痫发作转入医院儿科重症监护室(PICU);体重为2,440克(-3 SD),头围为32厘米(-3 SD)。查体时发现其前囟门(0.5×0.5 厘米)有颅骨畸形且张力过大。食指和拇指的关节挛缩。肝功能、血糖、肾功能和新生儿串联质谱筛查等常规检查结果均正常,且通过了听觉脑干反应测试。核磁共振成像显示胼胝体较薄,髓鞘化程度低(如图2),颅面比例下降。没有发现其他异常情况。她在进入PICU一周后因呼吸衰竭去世。

图2. 患儿2月龄时的MRI显示其胼胝体很薄(A),

髓鞘化程度低(B)。

研究方法

研究人员使用了IDT 埃德特公司的xGen杂交捕获系统的Exome Research Panel对家系三人进行了全外显子组靶向捕获。xGen Exome Research Panel 由415,115条单独合成且经过质控检验的xGen Lockdown探针组成。探针组跨越人基因组的34 Mb目标区域(19,433个基因),并且覆盖39 Mb的探针空间(即由探针覆盖的基因组区域)。探针是使用全新的“捕获感知”(capture-aware)算法进行设计的,并进行了专有的脱靶分析,确保实现最完整的设计覆盖度。探针组中的所有探针均严格按照 ISO 13485 标准进行生产。每条探针均经过质谱法和双定量测量检验,确保探针的质量及在探针库中具有适当的代表性。

经捕获的文库在Illumina NovaSeq 6000测序平台进行测序,发现先证者的SMPD4基因(NM_017951.4)中携带有一个纯和的无义变异c.1347C>G(p.Tyr449*),其母亲为携带有该变异的杂合子,而父亲则并不携带该变异,该结果经Sanger测序确认(如图3)。没有发现其他可疑的变异。随后的CNV分析显示该患者还携带有一个来自父系的344kb的片段缺失(Chr2 [GRCh37]: g.130877574_131221737del),这一缺失范围则覆盖了整个SMPD4基因(如图4)。由此确认患者所携带的c.1347C>G突变为一个半合子,而SMPD4则被确定为该患儿的致病基因。

图3. 先证者及其父母的Sanger测序结果。

图4. 先证者遗传自父系的2号染色体出现了344kb的片段缺失,

该缺失范围覆盖了整个SMPD4基因。

SMPD4基因介绍

SMPD4基因所编码的鞘磷脂磷酸二酯酶4(SMPD4)是一种会优先水解鞘磷脂的酶。而鞘磷脂作为神经系统正常运作的重要因子,当其合成降解的动态平衡被打破时,可能会导致多种神经系统疾病的发生。而SMPD4的缺失也被证明会导致成纤维细胞的异常有丝分裂和细胞凋亡的敏感性增加相关,且被证明与小头畸形和脑沟回减少相关。

迄今为止,已经在16个无血缘关系家庭的29个患者中发现了20种SMPD4致病变异(如图5);这些患者都出现了包括胎儿生长受限、小头畸形、关节发育不良、胼胝体变薄和脑沟回减少在内的部分或全部的症状。由于我们的案例所携带的两个突变都导致SMPD4蛋白无法合成,所以出现的新生儿发育迟缓、小头畸形和早期死亡的症状,都是NEDMABA较严重的临床表型。

图5.SMPD4基因转录本(NM_017951.4)和蛋白质序列上

所有已知致病变异。

虽然目前只有29名NEDMABA患者被报道,但如果基于gnomAD中导致SMPD4 LOF位点的携带频率进行计算的话,其患病率可能被低估了,这可能是由于NEDMABA的症状异质性较高,临床诊断难度较大所导致的。在许多国家,CMA芯片是先天性异常或发育障碍的一级遗传检测技术,但近年来随着全外显子组测序应用于遗传性疾病的诊断,越来越多患者的遗传病因被识别出来。尤其是在一系列基于WES的CNV检测算法成熟后,WES不仅可以识别SNP和小的Indel,大量外显子组水平的CNV也能够被扫描出来,且其精度远高于CMA芯片。因此,研究人员认为WES可以取代CMA,成为检测CNVs和诊断高度异质性疾病(如NEDMABA)的更高性价比的基因检测技术。而IDT埃德特的全外显子组产品Exome Research Panel V2以优异的品质能进一步助力提升遗传罕见病的检测水平。

综上所述,这项研究通过全外显子靶向捕获测序首次在中国报道了NEDMABA表型的病例,并为探究SMPD4在该综合征中的作用提供了进一步的临床与分子证据。

原文链接

Ji W, Kong X, Yin H, Xu J and Wang X (2022) Case Report: Novel Biallelic Null Variants of SMPD4 Confirm Its Involvement in Neurodevelopmental Disorder With Microcephaly, Arthrogryposis, and Structural Brain Anomalies. Front. Genet. 13:872264. doi: 10.3389/fgene.2022.872264

关于IDT埃德特

Integrated DNA Technologies, Inc. (IDT埃德特) 是丹纳赫集团(Danaher Corporation,纽约证交所代码:DHR)生命科学平台旗下的一家运营公司。IDT埃德特致力于面向生命科学界开发、生产并销售核酸产品,为学术与商业研究、农业、医疗诊断和药物开发等领域提供支持。IDT埃德特 开发了多项针对基因组应用的专利技术,涵盖二代测序、CRISPR 基因组编辑、合成生物学、数字 PCR 以及 RNA 干扰。通过GMP服务,IDT埃德特生产的产品被科学家用于研究多种形式的癌症以及各类遗传性和传染性疾病。作为定制核酸生产领域的优秀厂商,IDT埃德特为超过 130,000 名生命科学研究人员提供服务。

IDT埃德特创立于1987年,其生产总部位于美国爱荷华州科勒尔维尔,并在美国加利福尼亚州圣地亚哥、美国北卡罗来纳州三角研究园、比利时鲁汶以及新加坡等地设有生产工厂。更多信息,请关注“IDT埃德特”微信公众号或访问www.idtdna.com。

关于丹纳赫生命科学

丹纳赫是全球生命科学服务领域的专家,丹纳赫致力于以优质的产品与服务帮助客户加速生命科学领域的研究,解决在分析领域所遇到的问题和挑战,促进医疗诊断发展,提高实验室生产力。丹纳赫的企业使命是成就生命无限潜能。丹纳赫的产品旨在帮助全球人们生活得更健康、更安全、更舒心。丹纳赫生命科学中国区成立于2019年6月1日,旨在扎根中国市场,为中国的用户提供更好的产品和服务。丹纳赫生命科学中国区的愿景是“聚焦生命,聚力共赢”,以“共享全球科技,成就全民健康”为使命,着力于打造全方位的的精准医学和生物制药整体化解决方案。目前平台企业包括Integrated DNA Technologies Inc埃德特生物科技有限公司、贝克曼库尔特商贸(中国)有限公司、美谷分子仪器(上海)有限公司、上海爱博才思分析仪器贸易有限公司、天津博纳艾杰尔科技有限公司、徕卡显微系统(上海)贸易有限公司和颇尔(中国)有限公司。

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    2022-11-19 snf701207
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    2023-01-08 cy0324
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    2023-05-09 canlab
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