CAJ | 학술논문

目的对临床诊断为Joubert综合征的一家系进行临床和遗传学分析,明确其基因诊断以提供遗传咨询和产前诊断服务.方法以2013年深圳市妇幼保健院门诊临床诊断为Joubert综合征的一家系为研究对象,采集了该家系的先证者和患病胎儿的病史,采用目标序列捕获及新一代测序技术,对该家系先证者、患病胎儿及其父母双亲进行基因检测,采用Sanger测序法对发现的可能的致病突变进行家系成员验证,结合临床症状体征和综合检测结果,对该家系的Joubert综合征进行临床和分子遗传学分析.结果先证者婴儿期表现为发作性呼吸急促、肌张力增高,无异常的眼球运动,颅脑MRI提示磨牙征,后发展为共济失调、肌张力减退、明显的智力低下和生长发育迟缓,伴上睑下垂,暂时未发现肝肾功能及视力异常;妊娠中期彩超及MRI提示患病胎儿脑积水征象,无外观畸形.先证者及胎儿同时遗传了分别来自其父亲的CC2D2A基因c.2999A＞ T(p.Glu1000Val)错义突变和其母亲的CC2D2A基因20 ～21外显子的缺失,符合孟德尔复合杂合遗传.其中通过Sanger测序证实c.2999A＞ T(p.Glu1000Val)突变遗传自其父亲,先证者母亲该位点无突变.结论 Joubert综合征在胎儿期中-晚期可体现为脑积水,出生后婴儿期异常的呼吸,也可能表现出肌张力增高,头颅MRI体现为磨牙征,随着年龄增长表现出双侧肢体肌张力降低、共济失调、智力低下和生长发育迟缓,伴上睑下垂;综合临床病史和分子遗传学检测结果可推测CC2D2A基因的c.2999A＞ T(p.Glu1000Val)突变和20～21外显子的缺失复合杂合变异可能是该Joubert综合征家系的致病原因.
목적 대림상진단위Joubert종합정적일가계진행림상화유전학분석,명학기기인진단이제공유전자순화산전진단복무.방법 이2013년심수시부유보건원문진림상진단위Joubert종합정적일가계위연구대상,채집료해가계적선증자화환병태인적병사,채용목표서렬포획급신일대측서기술,대해가계선증자、환병태인급기부모쌍친진행기인검측,채용Sanger측서법대발현적가능적치병돌변진행가계성원험증,결합림상증상체정화종합검측결과,대해가계적Joubert종합정진행림상화분자유전학분석.결과 선증자영인기표현위발작성호흡급촉、기장력증고,무이상적안구운동,로뇌MRI제시마아정,후발전위공제실조、기장력감퇴、명현적지력저하화생장발육지완,반상검하수,잠시미발현간신공능급시력이상;임신중기채초급MRI제시환병태인뇌적수정상,무외관기형.선증자급태인동시유전료분별래자기부친적CC2D2A기인c.2999A＞ T(p.Glu1000Val)착의돌변화기모친적CC2D2A기인20 ～21외현자적결실,부합맹덕이복합잡합유전.기중통과Sanger측서증실c.2999A＞ T(p.Glu1000Val)돌변유전자기부친,선증자모친해위점무돌변.결론 Joubert종합정재태인기중-만기가체현위뇌적수,출생후영인기이상적호흡,야가능표현출기장력증고,두로MRI체현위마아정,수착년령증장표현출쌍측지체기장력강저、공제실조、지력저하화생장발육지완,반상검하수;종합림상병사화분자유전학검측결과가추측CC2D2A기인적c.2999A＞ T(p.Glu1000Val)돌변화20～21외현자적결실복합잡합변이가능시해Joubert종합정가계적치병원인.
Objective To confirm the genetic diagnosis for providing services for genetic counseling and prenatal diagnosis,we analyzed the clinical and genetic data of a pedigree which is clinically diagnosed as Joubert syndrome.Method A Joubert syndrome pedigree was enrolled as subject of this study from our hospital's outpatients in 2013.Following the medical history collection of the proband and the suffering fetus,target sequence capture and the next-generation sequencing technology were used for the proband and the suffering fetus to find the causative genes and sanger sequencing for the members of the pedigree to check and verify if the inherited mutations are in accordance with the Mendelian inheritance.Combining the clinical symptoms and signs with the total testing results,we analyzed the Joubert syndrome pedigree clinically and genetically.Result The proband showed abnormal respiratory patterns (neonatal tachypnea)and hypertonia without abnormal eye movements,and reflected the molar tooth sign on the magnetic resonance imaging.And afterwards the patient developed hypotonia,ataxia,growth and intellectual disability accompanied by congenital blepharoptosis.There were no any symptoms and signs of liver,kidney and eyesight abnormalities so far.The affected fetus showed hydrocephalus by the auxiliary examination during the second trimesters of pregnancy without any appearance deformities.Both the proband and the affected fetus carried a missense mutation of CC2D2A gene c.2999A ＞ T (p.Glu1000Val) from their father and carried the deletion of exon 20-21 on the same gene.Both variations were confirmed to be the Mendelian genetic compound heterozygous pattern.Whereas,the missense mutations c.2999A ＞ T(p.Glul000Val) on the CC2D2A gene have been proved to be inherited from the proband's father and the proband as well as the affected fetus.However,the proband's mother was normal at this locus of CC2D2A gene.The missense mutations c.2999A ＞ T (p.Glu1000Val) have been confirmed to accord with Mendelian inheritance.Conclusion The Joubert syndrome patient may show hypertonia in the early postnatal days as a result of hydrocephalus during the second and third trimesters of pregnancy besides manifesting hypotonia,ataxia,growth and intellectual disability markedly with age accompanied by the congenital blepharoptosis and revealing the molar tooth sign on the magnetic resonance imaging,considering the medical history and the whole testing results,the compound heterozygous mutations of c.2999A ＞ T(p.Glu1000Val)and deletion of exon 20-21 of CC2D2A gene in the pedigree may be the causal gene mutations.