摘要
目的分析4个Currarino综合征(CS)家系中患者的临床表型与遗传学特点。方法纳入4个CS家系5例患者,收集先证者病历并分析其临床表型特点,完善家属相关检查。采集先证者及其父母的外周血样本提取DNA,通过高通量测序及Sanger测序验证检测MNX1基因致病突变,回顾分析既往携带相同点突变或近似缺失的CS患者临床信息。结果临床表型分析显示4个CS家系的先证者中3例为散发性病例,1例为家族性病例,家族性病例的母亲也确诊为CS,临床分型5例患者中3例为完全型,2例为轻型,所有患者均有骶骨畸形和肛门直肠畸形表现。高通量测序检出3种来自不同家系的MNX1基因致病突变,包括1个错义突变(p.R293W)为母源性遗传、1个移码突变(p.R19Tfs*37)为父源性遗传和1个位于染色体7q36区域的拷贝数缺失(0.219 Mb)为新发突变。另有1个家系虽未检出MNX1基因致病突变,但检出1个SHH基因的错义突变(p.R163H)。家族性病例中检出的MNX1基因错义突变p.R293W位于高度保守的同源异形盒结构域内。回顾既往CS病例发现移码突变为热点突变,曾在8个CS病例中被报道。结论4个Currarino综合征(CS)家系分析揭示患者的临床表型异质性。检出3个MNX1基因致病突变并发现1个热点突变,进一步丰富了CS的临床表型谱及候选基因变异谱。
Objective To investigate the clinical manifestations and genotype characteristics of four pedigrees with Currarino syndrome(CS).Methods Four pedigrees with CS were enrolled,including 5 patients.Medical records of the probands were collected,their family members were examined and the clinical manifestations of all patients were analyzed.DNA was extracted from blood samples of the probands and their parents,and pathogenic mutations in MNX1 were tested with next-generation sequencing(NGS)and Sanger sequencing.The clinical information of previously reported patients with the same mutation or similar deletion was reviewed and analyzed.Results Clinical phenotypic analysis showed that among the four pedigrees with CS,three probands were sporadic and one was familial,and the mother of the familial case was also diagnosed as CS.Of all five patients,three cases were complete CS and two cases were mild CS.Three pathogenic mutations in MNX1 from different pedigrees were found by NGS,including a maternal inherited missense mutation(p.R293W),a paternal inherited frameshift mutation(p.R19Tfs*37)and a de novo copy number deletion(0.219 Mb)located in 7q36.In the remaining pedigree,a missense mutation in SHH(p.R163H)was found although no pathogenic mutation in MNX1 was detected.The missense mutation detected in the familial case was located in the highly conserved homeobox domain.A review of the clinical manifestations of previously reported patients with CS indicated that the frameshift mutation was a hotspot mutation,which had been reported in eight unrelated CS cases.Conclusion The CS patients of four pedigrees manifest the heterogeneity of clinical phenotype,and three pathogenic mutations in MNX1 are detected with one hotspot mutation,which expands the phenotype spectrum and candidate gene variant related to CS.
作者
刘凌娅
张震
李颀
耿园园
李龙
姜茜
LIU Lingya;ZHANG Zhen;LI Qi;GENG Yuanyuan;LI Long;JIANG Qian(Department of Medical Genetics,Capital Institute of Pediatrics,Beijing 100020,China;Department of General Surgery,Capital Institute of Pediatrics Affiliated Children’s Hospital)
出处
《山西医科大学学报》
CAS
2022年第12期1598-1605,共8页
Journal of Shanxi Medical University
基金
国家自然科学基金资助项目(82070532)
北京市属医学科研院所公益发展改革试点项目(京医研2019-11)。
作者简介
刘凌娅,女,1997-01生,在读硕士,E-mail:ivglly@sina.com;通讯作者:姜茜,E-mail:teaco@126.com。
