一个鳃-耳-肾综合征家系EYA1基因新致病性变异

A New Pathogenic Variation of EYA1 Gene in a Family with BOR Syndrome

王贺贺;孙敬武;万光伦;陈浩;李万举;赵婉;潘春晨;

1:安徽医科大学附属省立医院耳鼻咽喉头颈外科

2:中国科学技术大学附属第一医院(安徽省立医院)耳鼻咽喉头颈外科

摘要
目的研究一个鳃-耳-肾综合征(branchio-oto-renal, BOR)家系的临床表型及遗传学特征。方法通过家系调查、临床检查和遗传学特征分析,对一个鳃-耳-肾综合征家系的临床表型及致病原因进行系统研究,提取家系成员的外周血DNA,采用遗传性耳聋基因芯片进行最常见的GJB2(135 del G、176 del 16、299 del AT、235 del C)、GJB3(538 c>T)、SLC26A4(2168A>G、IVS7-2A>G)、mtDNA12SrRNA(1494C>T、1555C>T)4个基因9个耳聋位点检测,利用Sanger法进行基因测序,采用蛋白功能预测软件SIFT、PolyPhen_2和REVEL进行变异致病性的预测。结果该家系共有3代9人,4人患病,所有患者均有不同程度的听力损失;先证者(III-3)、其姐姐(III-1)和其母亲(II-2)均有右侧的肾异常;遗传性耳聋基因芯片检测结果未发现最常见的4个耳聋基因突变;Sanger测序法基因检测结果显示,先证者(III-3)、患者II-2、III-1及III-2的EYA1基因c.889C>T(p.R297X)突变,为无义突变,均为杂合变异,变异来源于II-2,II-1(先证者父亲)未发现该位点的变异。利用蛋白功能预测软件SIFT、PolyPhen_2和REVEL进行EYA1基因变异致病性的分析,结果均显示为未知。结论本研究首次检测出中国BOR综合征人群中EYA1基因c.889C> T (p.R297X)位点的致病性突变。
关键词
鳃-耳-肾综合征;EYA1基因;基因突变;肾异常
基金项目(Foundation):
国家自然科学基金青年项目(81800911H1304);; 安徽省自然科学基金青年项目(1808085QH248);; 国家自然科学青年基金(81600793)
作者
王贺贺;孙敬武;万光伦;陈浩;李万举;赵婉;潘春晨;
参考文献

1 Parkes WJ,Cushing SL,Blaser SI,et al.Transmastoid access in branchio-oto-renal syndrome:a reappraisal of computed tomography imaging[J].Int J Pediatr Otorhinolaryngol,2018,114(11):92-96.

2 Kim HR,Song MH,Kim MA,et al.Identification of a novel nonsynonymous mutation of EYA1 disrupting splice site in a Korean patient with BOR syndrome[J].Mol Biol Rep,2014,41(7):4321-4327.

3 Gigante M,d'Altilia M,Montemurno E,et al.Branchio-Oto-Renal Syndrome (BOR) associated with focal glomerulosclerosis in a patient with a novel EYA1 splice site mutation[J].BMC Nephrol,2013,14(3):60-64.

4 Safaya A,Shah S,Dlshi B.Unilateral branchial sinus with unilateral renal agenesis:a variant of BOR syndrome?A case report[J].Indian J Otolaryngol Head Neck Surg,2014,66(1):356-358.

5 Zou D,Silvius D,Fritzsch B,et al.Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes[J].Development,2004,131(22):5561-5572.

6 Bertucci E,Mazza V,Lugli L,et al.Prenatal diagnosis and follow-up of a case of branchio-oto-renal syndrome displays renal growth impairment after the second trimester[J].J Obstet Gynaecol Res,2015,41(11):1831-1834.

7 Williams LE,Sohner MT,Sibley RC,et al.Multimodality depiction of findings in branchio-oto-renal syndrome:two case reports[J].Acta Radiol Open,2019,8(7):1-3.

8 Chang EH,Menezes M,Meyer NC,et al.Branchio-oto-renal syndrome:the mutation spectrum in EYA1 and its phenotypic consequences[J].Hum Mutat,2004,23(6):582-589.

9 Unzaki A,Morisada N,Nozu K,et al.Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome[J].J Hum Genet,2018,63(5):647-656.

10 Je menica J,Bajec OA.Branchiootorenal and branchiooculofacial syndrome[J].J Craniofac Surg,2015,26(1):30-31.

11 Orten DJ,Fischer SM,Sorensen JL,et al.Branchio-oto-renal syndrome (BOR):novel mutations in the EYA1 gene,and a review of the mutational genetics of BOR[J].Hum Mutat,2008,29(4):537-544.

12 Klingbeil KD,Greenland CM,Arslan S,et al.Novel EYA1 variants causing Branchio-oto-renal syndrome[J].Int J Pediatr Otorhinolaryngol,2017,98(7):59-63.

13 Abdelhak S,Kalatzis V,Heilig R,et al.A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family[J].Nat Genet,1997,15(2):157-164.

14 Chen PH,Liu HJ,Lin Y,et al.EYA1 mutations leads to branchio-oto syndrome in two Chinese Han deaf families[J].Int J Pediatr Otorhinolaryngol,2019,123(8):141-145.

15 Wang SH,Wu CC,Lu YC,et al.Mutation screening of the EYA1,SIX1,and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome[J].Laryngoscope,2012,122(5):1130-1136.

16 Li G,Shen Q,Sun L,et al.de novoA and novel mutation in the gene in a Chinese child with branchio-oto-renal syndrome[J].Intractable Rare Dis Res,2018,7(1):42-45.

17 Wang YG,Sun SP,Qiu YL,et al.A novel mutation in EYA1 in a Chinese family with Branchio-oto-renal syndrome[J].BMC Med Genet,2018,19(1):139-146.

18 Men M,Li W,Chen HS,et al.Identification of a novel CNV at 8q13 in a family with branchio-oto-Renal syndrome and epilepsy[J].Laryngoscope,2020,130(2):526-532.