一个常染色体显性遗传型地中海热家系的临床及遗传学分析

Clinical and genetic analysis of a family with autosomal dominant-familial Mediterranean fever

目的分析1个由MEFV基因变异所致的常染色体显性遗传型地中海热(autosomal dominant-familial Mediterranean fever,AD-FMF)家系的临床及遗传学特点。方法先证者为男性,5岁,以"发作性无菌性脑膜炎"作为首发表现,症状表现为发作性发热伴头痛呕吐;其母亲、胞兄及胞姐均存在类似发作性发热。提取该家系成员外周血DNA,应用全外显子基因组测序法检测相关基因变异,并通过Sanger测序法验证变异。对可疑变异进行生物信息学分析。结果经全外显子基因组测序分析发现,先证者MEFV基因上第10外显子存在一个c.2229C>G(p.Phe743Leu)错义变异,该变异在其母亲、胞兄及胞姐中均有检出。c.2229C>G虽为国内外未报道的错义变异,但其导致的氨基酸水平的改变(p.Phe743Leu)既往在阿拉伯发病人群中有报道(PS1);该变异在常见正常人群数据库中不存在(PM2),且经Mutationtaster、PROVEAN、PolyPhen-2等变异预测软件预测结果均提示为有害变异;经PubMed BLAST系统分析MEFV基因编码蛋白pyrin第743位氨基酸的改变可影响SPRY_PRY_TRIM20及SPRY_superfamily结构域的完整性;同时经计算机模拟对蛋白3D结构建模分析发现,该氨基酸的改变可导致pyrin蛋白原有空间结构发生改变,原有功能丧失(PP3)。根据美国医学遗传学与基因组学学会序列变异解释指南判定该家系检出变异为可能致病性变异(PS1+PM2+PP3)。结论MEFV基因c.2229C>G(p.Phe743Leu)可能为该家系罹患AD-FMF的致病原因,以"发作性无菌性脑膜炎"作为主要临床表现在AD-FMF患者中较罕见,国内尚未见报道,分析该家系成员的临床表型及基因变异特点有助于提高国内医师对该病的认识。

Objective To analyze a pathogenic variant of MEFV gene in a family with autosomal dominant-familial Mediterranean fever(AD-FMF).Methods A 5 year-old boy presented with recurrent aseptic meningitis and his major symptoms included recurrent fever with headache and vomiting.His family members including his mother,sister and brother also had recurrent fever.A genetic disease was considered.DNAs were extracted from patient and all his family members’blood samples.Whole-exome sequencing was performed to identify putative pathogenic variants that can explain this family’s condition and Sanger sequencing was conducted.The impact of detected variants were predicted and validated by bioinformatics.Results A missense variant c.2229C>G(p.Phe743Leu)in MEFV gene was identified in the proband and his family members including his mother,sister and brother.This variant had not been reported in China previously,but the locus of it had already been reported in Arabic patient with AD-FMF(PS1).This variant was absent in major allele frequency databases(PM2)and had been predicted to be pathogenic based on Mutationtaster,PROVEAN and PolyPhen-2.In addition,the change of amino acid,locating in 743 locus of pyrin protein,encoding by MEFV gene,was found to cause SPRY_PRY_TRIM20 and SPRY_superfamily domain destroyed and finally influenced the fuction of pyrin protein.On the other hand,using UCSF chimera software,we find the variant c.2229C>G(p.Phe743Leu)can induce serious influence to the spatial structure of pyrin protein and loss of protein fuction(PP3).According to the ACMG variant classification guideline,the variant c.2229C>G(p.Phe743Leu)in MEFV was classified as likely pathogenic(PS1+PM2+PP3).Conclusion The condition of this AD-FMF family may be attributed to the missense variant c.2229C>G(p.Phe743Leu)in MEFV gene.The recurrent aseptic meningitis was a very rare manifestation in AD-FMF patients and had not been reported in China previously.The clinical and genetic findings of the present study are helpful for the further understanding of AD-FMF.