FBN1和FGFR3基因突变导致马凡综合征和软骨发育不良罕见共病1家系基因型与临床表型的关系
Relationship of genotype and clinical phenotype in a family with rare comorbidity of Marfan syndrome and hypochondroplasia caused by FBN1 and FGFR3 gene mutations
唐巧茵 1蒋劲嵩 1曹桂芝 2张莉雪 1赵晨玥 1郭荣 2薛慧琴2
作者信息
- 1. 山西医科大学研究生学院儿科医学系,山西太原 030001
- 2. 山西省儿童医院山西省妇幼保健院细胞遗传室,山西太原 030013
- 折叠
摘要
目的 分析FBN1和FGFR3基因突变导致马凡综合征(MFS)和软骨发育不良(HCH)罕见共病1家系的临床资料,探讨其基因型与临床表型的关系.方法 2021年6月13日山西省儿童医院诊治1个MFS和HCH罕见共病家系,收集该家系成员临床资料,采用高通量测序法对先证者及其母亲进行全外显子组测序并鉴定基因突变位点,采用Sanger测序法对家系成员突变位点进行验证.应用Uniprot、Jalview软件对突变位点进行保守性分析,采用ACMG指南评级评估突变致病性.结果 先证者主要临床表现为身材高大、漏斗胸、晶状体脱位等,先证者母亲和姐姐主要临床表现为身材矮小、弓形腿、晶状体脱位等.先证者存在FBN1基因c.364C＞T(p.Arg122Cys)杂合错义突变,导致FBN1基因5号外显子EFG样结构域中第122位精氨酸(Arg)变为半胱氨酸(Cys);先证者母亲和姐姐存在FBN1基因c.364C＞T(p.Arg122Cys)和FGFR3基因c.1620C＞G(p.Asn540Lys)杂合错义突变,其中FGFR3基因突变导致12号外显子TK1结构域中第540位天冬酰胺(Asn)变为赖氨酸(Lys).FBN1基因c.364位点在4个物种(人、小鼠、牛、猪)、FGFR3基因c.1620位点在4个物种(人、原鸡、小鼠、非洲爪蟾)中均高度保守,ACMG指南评级分别为致病、可能致病;FBN1基因突变导致先证者患MFS,FBN1合并FGFR3基因突变导致先证者母亲和姐姐罕见共患MFS和HCH.2021年12月先证者夫妇行体外受精-胚胎移植术,2022年10月娩出1名健康男婴.结论 先证者身材高大由FBN1基因突变引起,先证者母亲和姐姐身材矮小等骨骼系统临床表现与FGFR3基因突变有关.
Abstract
Objective To observe the clinical data of a family with rare comorbidity of Marfan syndrome and hypochondroplasia(HCH)caused by FBN1 and FGFR3 gene mutations,and to investigate the relationship between genotype and clinical phenotype.Methods A family with a rare comorbidity of Marfan syndrome and HCH caused by FBN1 and FGFR3 gene mutations was diagnosed and treated in Shanxi Provincial Children's Hospital on June 13,2021,and the clinical data were collected from the family members.The proband and his mother received whole exome sequence by high throughput sequencing method to identify the gene mutation sites.The mutation sites of the family members were verified by PCR-Sanger sequencing.A conservative analysis on mutation sites was done by Uniprot and Jalview software,and ACMG guideline was applied to evaluate their pathogenicity.Results The proband showed tall stature,funnel chest,and dislocation of lens while his mother and sister showed short stature,gonyectyposis,and dislocation of lens.Heterozygous missense mutation of c.364C＞T(p.Arg122Cys)in FBN1 gene in the proband caused the conversion of No.122 Arg to Cys in exon 5 of FBN1 gene EKG-like domain.Heterozygous missense mutations of c.364C＞T(p.Arg122Cys)in FBN1 gene and c.1620C＞G(p.Asn540Lys)in FGFR3 gene were found in the proband's mother and sister,in which FGFR3 gene mutation caused the conversion of No.540 Asp to Lys in exon 12 of FGFR3 gene TK1 domain.The c.364 site of FBN1 gene in four species(human,mouse,bovin,pig)and c.1620 site of FGFR3 gene in four species(human,chick,mouse,xenla)were highly conserved,and they were pathogenic and likely pathogenic respectively in the ACMG guideline rating.The FBN1 gene mutation led to Marfan syndrome in the proband,and FBN1 combined with FGFR3 gene mutations resulted in rare comorbidity of MFS and HCH in the proband's mother and sister.The proband and his wife received in vitro fertilization-embryo transfer in December 2021 and delivered a healthy boy in October 2022.Conclusion The tall stature of the proband is caused by FBN1 gene mutation,while the clinical manifestations in the skeletal system of the proband's mother and sister such as short stature are more correlated with FGFR3 gene mutation.
关键词
马凡综合征/软骨发育不良/罕见共病/FBN1基因/FGFR3基因/基因型/表型Key words
Marfan syndrome/hypochondroplasia/rare comorbidity/FBN1 gene/FGFR3 gene/genotype/phenotype引用本文复制引用
基金项目
国家人口与生殖健康科学数据中心工程项目(2005DKA32408)
山西省留学人员科技活动择优资助项目(201919)
山西省2020年度"四个一批"科技兴医创新计划项目医学遗传学研究委级重点实验室(2020SYS24)
出版年
2024
NETL
NSTL
万方数据