VLDLR变异导致Blake’s陷窝囊肿合并小脑蚓部发育不良胎儿的遗传学分析  

Genetic analysis of a fetus with VLDLR mutation causing Blake’s pouch cyst comorbid with vermian hypoplasia

作　　者：唐冬松 任建宇[2] 李长龙[3] 杨树法[2] TANG Dongsong;REN Jianyu;LI Changlong;YANG Shufa(Clinic Laboratory Center,Beijing Youan Hospital,Capital Medical University,Beijing 100069,China;Prenatal Diagnostic Center,Beijing Obstetrics and Gynecology Hospital,Capital Medical University,Beijing Maternal and Child Health Care Hospital,Beijing 100026,China;Department of Genetics and Developmental Biology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China)

机构地区：[1]首都医科大学附属北京佑安医院临检中心,北京100069 [2]首都医科大学附属北京妇产医院/北京妇幼保健院产前诊断中心,北京100026 [3]首都医科大学基础医学院医学遗传学与发育生物学系,北京100069

出　　处：《中国优生与遗传杂志》2024年第12期2586-2591,共6页Chinese Journal of Birth Health & Heredity

基　　金：国家自然科学基金(32070537);北京市自然科学基金-北京市教育委员会重点项目(KZ202110025037);医学科学创新中心科研培育项目(CX24PY04)。

摘　　要：目的分析1例Blake’s陷窝囊肿合并小脑蚓部发育不良的遗传学病因。方法收集胎儿B超、MRI、尸检、染色体核型分析、CNV-seq检查以及全外显子组测序结果,并利用Sanger测序对致病变异位点进行确认。检索The Human Protein Atlas数据库、Monarch数据库以及Simple ClinVar数据库,分析候选致病基因与疾病的关系。构建致病基因野生型以及变异型蛋白3D结构,利用Gromacs软件对野生型和变异型致病基因蛋白进行分子动力学模拟。结果胎儿在23周、25周以及28周依次出现Blake’s囊肿、小脑发育不良、双侧侧脑室室管膜下囊肿。羊水染色体核型分析以及CNV-seq结果未见异常。全外显子组测序显示胎儿VLDLR复合杂合变异:c.262C>T(p.R88*)和c.670G>A(p.E224K)。这两个未见报道的可能致病性变异分别遗传自父、母亲,且均位于VLDLR的LDL受体A家族结构域。c.670G>A(p.E224K)可以影响VLDLR的RMSD、Gyrate、蛋白内氢键数量以及第225氨基酸位置的二级结构。结论VLDLR基因c.262C>T(p.R88*)和c.670G>A(p.E224K)复合杂合变异是导致Blake’s陷窝囊肿合并小脑蚓部发育不良的病因。Objective Analysis of the genetic etiology of a case of Blake’s pouch cyst comorbid with vermian hypoplasia.Methods Results of ultrasound,MRI,autopsy of aborted fetuses,chromosome karyotyping analysis,CNV-seq,and whole exome sequencing were collected.The pathogenic variant mutations were confirmed via Sanger sequencing.The Human Protein Atlas database,Monarch database,and Simple ClinVar database were searched to analyze the relationship between candidate pathogenic genes and diseases.The 3D structures of wild-type and mutant genes were constructed.The molecular dynamics simulations of wild-type and mutant proteins were performed through Gromacs software.Results The fetus developed Blake’s cyst,vermian hypoplasia,and bilateral subventricular cysts at 23 weeks,25 weeks,and 28 weeks in turn.Amniotic fluid chromosome karyotype analysis and CNV-seq results showed no abnormalities.Whole exome sequencing revealed the fetus carried compound heterozygous variants in VLDLR:c.262C>T(p.R88*)and c.670G>A(p.E224K).These two likely pathogenic variants,which have not been previously reported,were inherited from the father and mother respectively.Both variations located in the LDL receptor A family domain of VLDLR.The c.670G>A(p.E224K)variant may affect the RMSD,gyration,number of intramolecular hydrogen bonds,and secondary structure at the position of the 225th amino acid in VLDLR.Conclusion The compound heterozygous variants c.262C>T(p.R88*)and c.670G>A(p.E224K)in VLDLR lead to Blake’s pouch cyst comorbid with vermian hypoplasia.

关 键 词：Blake’s陷窝囊肿 小脑蚓部发育不良 极低密度脂蛋白受体 产前诊断 

分 类 号：R73[医药卫生—肿瘤]