Floating-harbor综合征的临床及遗传特点(附2例分析)

Clinical and genetic characteristics of Floating-harbor syndrome(report of two cases)

目的总结SRCAP基因突变引起的常染色体显性遗传病Floating-harbor综合征(FHS)的临床及遗传特点。方法回顾性分析2例FHS患者的临床资料及遗传资料。结果2例患者均身材矮小,面容异常(三角脸、深眼窝、长睫毛、鼻头宽大呈球形、嘴型宽大、下唇略外翻、鼻小柱低垂、短人中、低耳位),骨龄落后,语言发育落后并伴有骨骼畸形。全外显子组基因测序发现SRCAP基因2个新生无义变异,其中患者1为新发现的无义变异,文献数据库中未有该位点的相关性报道。患者1第34号外显子c.7255C>T(p.Q2419X)杂合无义变异,患者2第34号外显子c.7466C>G(p.S2489X)杂合无义变异,Sanger测序验证2例患者的父母均未携带这2个位点的变异。2个无义变异经MutationTaster和PROVEAN预测结果均提示为有害变异。利用Clustal Omega网站分析显示SRCAP基因编码蛋白第2419位Gln和第2489位Ser在哺乳动物中高度保守。Pubmed CD-search系统分析显示SRCAP蛋白在2419位或2489位终止编码导致蛋白质截断突变,虽未影响蛋白的保守结构域,但可导致3个AT-hook结构域丧失。根据ACMG指南,这两个变异初步判定为致病性变异。结论FHS患者的临床特点为面容特殊、身材矮小、骨龄落后、语言表达障碍,遗传特点为是SRCAP基因的杂合无义突变,该突变可导致蛋白截断突变,具有致病性。

Objective To summarize the clinical and genetic characteristics of autosomal dominant disease Floating-harbor syndrome(FHS)caused by SRCAP gene mutation.Methods The clinical and genetic data of 2 patients with FHS were analyzed retrospectively.Results Two male patients were characterized by the typical facial dysmorphic features(triangular face,deep-set eyes,long eyelashes,prominent nose,short philtrum,wide and low-hanging columella,wide mouth with a slightly everted lower lip and low-set ears),short stature with significantly delayed bone age,expressive language delay,and skeletal dysplasia.Whole exome sequencing found two de novo nonsense variants in the SRCAP gene,and the mutation site of patient 1 was not reported in the literature database.The heterozygous nonsense mutation sites of both patients were located in exon 34,which were c.7255 C>T(p.q2419 x,patient1)and c.7466 C>G(p.s2489 x,patient2),respectively.Sanger sequencing verified that neither parent of both patients carried the mutation.The two mutations were predicted to be pathogenic based on MutationTaster and PROVEAN.Clustal Omega website analysis showed that Gln 2419 and Ser2489 in SRCAP residues were highly conserved in mammals.PubmedCD-search analysis showed that the truncation mutation of SRCAP protein caused by these two site mutations did not affect the conserved domain of the protein.According to PubmedCD-Search systerm analysis,the truncation mutation of SRCAP protein caused by these two mutations,did not affect the conserved domain of the protein,but resulted in the loss of three AT-hook domains.According to ACMG,these two variants were determined to be pathogenic.Conclusions The clinical features of two cases with FHS are dysmorphic facial features,short stature,significantly delayed bone age,delayed language development and skeletal deformities.The genetic characteristics of both patients are heterozygous nonsense mutations in SRCAP gene,which could lead to protein truncation mutations and are pathogenic.