低频相关常染色体显性遗传耳聋家系的临床与遗传学特征分析
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摘要
目的通过研究4代遗传耳聋家系,分析家系成员临床表型、遗传特征,为致病基因鉴定、遗传咨询和婚育指导提供依据。方法对家系成员进行病史调查、查体、临床听力学检测和外周静脉血样本采集,绘制遗传图谱,分析听力学特征及家系遗传规律。结果调查1507327家系共51人,发现20人存在听力损失,其中直系亲属感音神经性耳聋15人,传导性耳聋2人,混合性耳聋1人,配偶感音神经性耳聋患者2人。直系亲属感音神经性耳聋患者中:男性6人,女性9人;发病年龄8到49岁,平均31.7岁;低频听力损失型4例,全频听力损失型11例;听力损失程度轻度2例,中度4例,中重度3例,重度5例,极重度1例;随年龄(x)增加平均听阈(y)逐渐增高(y=1.180x+4.886,R2=0.618,P=0.001);各代连续发病,每一代男女均可患病;在进行过听力测试的家系成员中,Ⅱ代患病率100%(1/1),Ⅲ代患病率61.11%(11/18),Ⅳ代患病率13.04%(3/23);Ⅱ代平均发病年龄35岁,Ⅲ代平均发病年龄32.45岁,Ⅳ代平均发病年龄27.67岁。结论此耳聋家系为低频听力损失起病、逐渐加重、最终累及全频的非综合征型感音神经性耳聋。遗传方式为常染色体显性遗传,外显率逐渐降低,发病年龄逐渐提前。后续研究可针对低频相关的耳聋基因进行致病基因的鉴定。
Objective To report clinical phenotypes and genetic characteristics of a four-generation Chinese family with nonsyndromic autosomal dominant hearing loss, to provide basis for identification of pathogenic genes, genetic counseling and marriage and parenting guidance. Method Pedigree of the family was draw, audiological and genetic characteristics were evaluated following clinical studies including kindred investigation and comprehensive physical examinations. Peripheral blood samples were collected. Result In the family, 20 of the 51 investigated members were found to have hearing impairment, including 15 with sensorineural hearing loss, 2 with conductive hearing, 1 with mixed hearing loss and 2 spouses with sensorineural hearing loss. Among the 15 family members with sensorineural hearing loss, 6 were males and 9 were females, with onset ages ranging from 8 to 49 years(mean = 31.7 years). Hearing loss affected low-frequencies in 4 cases and all frequencies in 11 cases. Hearing loss was mild in 2 cases, moderate in 4 cases, moderately severe in 3 cases, severe in 5 cases and extremely severe in 1 case. The average auditory threshold(y)increased gradually with age(x)(y = 1.180 x + 4.886, R squared = 0.618,P=0.001). All generations of the family were affected. Among the family members who received hearing tests, the rate of SNHL patients was 100%(1/1) in Generation Ⅱ, 61.11%(11/18) in Generation Ⅲ and 13.04%(3/23) in Generation Ⅳ. The average onset age was 35 years inGeneration Ⅱ, 32.45 years in Generation Ⅲ and 27.67 years in Generation Ⅳ. Conclusion This Pedigree is identified to be affected by autosomal dominant hereditary hearing loss featuring low frequency involvement at onset, which continues to progress to eventually affect the full frequency range. The penetrance appears to gradually decrease, with the onset age gradually become younger. Subsequent studies may focus on identifying the causative genes for the low-frequency deafness.
Objective To report clinical phenotypes and genetic characteristics of a four-generation Chinese family with nonsyndromic autosomal dominant hearing loss, to provide basis for identification of pathogenic genes, genetic counseling and marriage and parenting guidance. Method Pedigree of the family was draw, audiological and genetic characteristics were evaluated following clinical studies including kindred investigation and comprehensive physical examinations. Peripheral blood samples were collected. Result In the family, 20 of the 51 investigated members were found to have hearing impairment, including 15 with sensorineural hearing loss, 2 with conductive hearing, 1 with mixed hearing loss and 2 spouses with sensorineural hearing loss. Among the 15 family members with sensorineural hearing loss, 6 were males and 9 were females, with onset ages ranging from 8 to 49 years(mean = 31.7 years). Hearing loss affected low-frequencies in 4 cases and all frequencies in 11 cases. Hearing loss was mild in 2 cases, moderate in 4 cases, moderately severe in 3 cases, severe in 5 cases and extremely severe in 1 case. The average auditory threshold(y)increased gradually with age(x)(y = 1.180 x + 4.886, R squared = 0.618,P=0.001). All generations of the family were affected. Among the family members who received hearing tests, the rate of SNHL patients was 100%(1/1) in Generation Ⅱ, 61.11%(11/18) in Generation Ⅲ and 13.04%(3/23) in Generation Ⅳ. The average onset age was 35 years inGeneration Ⅱ, 32.45 years in Generation Ⅲ and 27.67 years in Generation Ⅳ. Conclusion This Pedigree is identified to be affected by autosomal dominant hereditary hearing loss featuring low frequency involvement at onset, which continues to progress to eventually affect the full frequency range. The penetrance appears to gradually decrease, with the onset age gradually become younger. Subsequent studies may focus on identifying the causative genes for the low-frequency deafness.
引文
1 Hilgert N,Smith RJ,Van Camp G.Forty-six genes causing nonsyndromic hearing impairment:which ones should be analyzed in DNA diagnostics[J]Mutat Res.2009,681(2-3):189-196.
2 International Organization for Standardization Acoustics:reference zero for the calibration of audiometric equipment-part 1:reference equivalent threshold sound pressure levels for pure tones and supra-aural earphones[J].International Organization for Standardization,Geneva,Switzerland.2000,BS EN ISO389-1.
3 International Organization for Standardization Acoustics:audiometric test methods,I:basic pure tone air and bone conduction threshold audiometry[J].International Organization for Standardization,Geneva,Switzerland.1998,ISO 8253-1.
4 Clark JG.Uses and abuses of hearing loss classification[J].ASHA.1981,23(7):493-500.
5 Morton NE.Genetic epidemiology of hearing impairment[J].Ann N Y Acad Sci.1991,630:16-31
6王秋菊,刘穹.常染色体显性遗传性耳聋(1)[J].听力学及言语疾病杂志.2016,24(02):213-216.Wang QJ,Liu Q.Autosomal dominant inheritant hearing loss(1)[J].Journal of Audiology and Speech Pathology.2016,24(02):213-216.
7 Lynch ED.Nonsyndromic Deafness DFNA1 Associated with Mutation of a Human Homolog of the Drosophila Gene diaphanous[J].Science.1997,278(5341):1315-1318.
8 Bespalova IN,Van Camp G,Bom SJ,et al.Mutations in the Wolfram syndrome 1 gene(WFS1)are a common cause of low frequency sensorineural hearing loss[J].Hum Mol Genet.2001,10(22):2501-2508.
9 Young TL,Ives E,Lynch E,Person R,et al.Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1[J].Hum Mol Genet.2001,10(22):2509-2514.
10 Modamio-Hoybjor S,Mencia A,Goodyear R,et al.A mutation in CCDC50,a gene encoding an effector of epidermal growth factor-mediated cell signaling,causes progressive hearing loss[J].Am J Hum Genet.2007,80(6):1076-1089.
11 Modamio-Hoybjor S,Moreno-Pelayo MA,Mencia A,et al.Anovel locus for autosomal dominant nonsyndromic hearing loss(DFNA44)maps to chromosome 3q28-29[J].Hum Genet.2003,112(1):24-28.
12 Zhao Y,Zhao F,Zong L,et al.Exome sequencing and linkage analysis identified tenascin-C(TNC)as a novel causative gene in nonsyndromic hearing loss[J].PLoS One.2013,8(7):e69549.
13 Fujikawa T,Noguchi Y,Ito T,et al.Additional heterozygous2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies[J].Laryngoscope.2010,120(1):166-171.
14 Sun Y,Cheng J,Lu Y,et al.Identification of two novel missense WFS1 mutations,H696Y and R703H,in patients with non-syndromic low-frequency sensorineural hearing loss[J].J Genet Genomics.2011,38(2):71-76.
15 Bai X,Lv H,Zhang F,et al.Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies[J].Am J Med Genet A.2014,164A(12):3052-3060.
16 Goncalves AC,Matos TD,Simoes-Teixeira HR,et al.WFS1 and non-syndromic low-frequency sensorineural hearing loss:a novel mutation in a Portuguese case[J].Gene.2014,538(2):288-291.
17 Wei Q,Zhu H,Qian X,et al.Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss[J].J Transl Med.2014,12:311.
18 Niu Z,Feng Y,Hu Z,et al.Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family[J].Int J Pediatr Otorhinolaryngol.2017,100:1-7.
19 Kobayashi M,Miyagawa M,Nishio SY,et al.WFS1 mutation screening in a large series of Japanese hearing loss patients:Massively parallel DNA sequencing-based analysis[J].PLoS One.2018,13(3):e0193359.
20 Gurtler N,Kim Y,Mhatre A,et al.Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1[J].J Mol Med(Berl).2005,83(7):553-560.
21 Stritt S,Nurden P,Turro E,et al.A gain-of-function variant in DI-APH1 causes dominant macrothrombocytopenia and hearing loss[J].Blood.2016,127(23):2903-2914.
22 Ganaha A,Kaname T,Shinjou A,et al.Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease[J].Am J Med Genet A.2017,173(10):2826-2830.
23 Neuhaus C,Lang-Roth R,Zimmermann U,et al.Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss(DFNA1)[J].Clin Genet.2017,91(6):892-901.
24 Snoeckx RL,Kremer H,Ensink RJ,et al.A novel locus for autosomal dominant non-syndromic hearing loss,DFNA31,maps to chromosome 6p21.3[J].J Med Genet.2004,41(1):11-13.
25 Moreno-Pelayo MA,Modamio-Hoybjor S,Mencia A,et al.DF-NA49,a novel locus for autosomal dominant non-syndromic hearing loss,maps proximal to DFNA7/DFNM1 region on chromosome 1q21-q23[J].J Med Genet.2003,40(11):832-836.
26 Gurtler N,Kim Y,Mhatre A,et al.DFNA54,a third locus for low-frequency hearing loss[J].J Mol Med(Berl).2004,82(11):775-780.
27 B?nsch D,Schmidt CM,Scheer P,et al.Ein neuer Genort für eine autosomal dominante,nichtsyndromale H?rst?rung(DF-NA57)kartiert auf Chromosom 19p13.2 undüberlappt mit DF-NB15[J].Hno.2008,56(2):177-182.
28 Starr A,Picton TW,Sininger Y,et al.Auditory neuropathy[J].Brain.1996,119(Pt 3):741-753.
29王秋菊,Starr A.听神经病:从发现到渐入精准[J].中华耳鼻咽喉头颈外科杂志.2018,53(3):161-171.Wang QJ,Starr A.Hereditary auditory neuropathies:stepping into precision management from the discovery[J].Chin J Otorhinolaryngol Head Neck Surg.2018,53(3):161-171.
30 Kim TB,Isaacson B,Sivakumaran TA,et al.A gene responsible for autosomal dominant auditory neuropathy(AUNA1)maps to13q14-21[J].J Med Genet.2004,41(11):872-876.
31王洪阳,王秋菊.目标区域捕获联合新一代测序技术在遗传性聋研究中的应用及发展前景[J].听力学及言语疾病杂志.2014,22(05):531-536.Wang HY,Wang QJ.Application and prospects of target region capture and next generation sequencing technology in inheritant deafness research.Journal of Audiology and Speech Pathology.2014,22(05):531-536.
2 International Organization for Standardization Acoustics:reference zero for the calibration of audiometric equipment-part 1:reference equivalent threshold sound pressure levels for pure tones and supra-aural earphones[J].International Organization for Standardization,Geneva,Switzerland.2000,BS EN ISO389-1.
3 International Organization for Standardization Acoustics:audiometric test methods,I:basic pure tone air and bone conduction threshold audiometry[J].International Organization for Standardization,Geneva,Switzerland.1998,ISO 8253-1.
4 Clark JG.Uses and abuses of hearing loss classification[J].ASHA.1981,23(7):493-500.
5 Morton NE.Genetic epidemiology of hearing impairment[J].Ann N Y Acad Sci.1991,630:16-31
6王秋菊,刘穹.常染色体显性遗传性耳聋(1)[J].听力学及言语疾病杂志.2016,24(02):213-216.Wang QJ,Liu Q.Autosomal dominant inheritant hearing loss(1)[J].Journal of Audiology and Speech Pathology.2016,24(02):213-216.
7 Lynch ED.Nonsyndromic Deafness DFNA1 Associated with Mutation of a Human Homolog of the Drosophila Gene diaphanous[J].Science.1997,278(5341):1315-1318.
8 Bespalova IN,Van Camp G,Bom SJ,et al.Mutations in the Wolfram syndrome 1 gene(WFS1)are a common cause of low frequency sensorineural hearing loss[J].Hum Mol Genet.2001,10(22):2501-2508.
9 Young TL,Ives E,Lynch E,Person R,et al.Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1[J].Hum Mol Genet.2001,10(22):2509-2514.
10 Modamio-Hoybjor S,Mencia A,Goodyear R,et al.A mutation in CCDC50,a gene encoding an effector of epidermal growth factor-mediated cell signaling,causes progressive hearing loss[J].Am J Hum Genet.2007,80(6):1076-1089.
11 Modamio-Hoybjor S,Moreno-Pelayo MA,Mencia A,et al.Anovel locus for autosomal dominant nonsyndromic hearing loss(DFNA44)maps to chromosome 3q28-29[J].Hum Genet.2003,112(1):24-28.
12 Zhao Y,Zhao F,Zong L,et al.Exome sequencing and linkage analysis identified tenascin-C(TNC)as a novel causative gene in nonsyndromic hearing loss[J].PLoS One.2013,8(7):e69549.
13 Fujikawa T,Noguchi Y,Ito T,et al.Additional heterozygous2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies[J].Laryngoscope.2010,120(1):166-171.
14 Sun Y,Cheng J,Lu Y,et al.Identification of two novel missense WFS1 mutations,H696Y and R703H,in patients with non-syndromic low-frequency sensorineural hearing loss[J].J Genet Genomics.2011,38(2):71-76.
15 Bai X,Lv H,Zhang F,et al.Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies[J].Am J Med Genet A.2014,164A(12):3052-3060.
16 Goncalves AC,Matos TD,Simoes-Teixeira HR,et al.WFS1 and non-syndromic low-frequency sensorineural hearing loss:a novel mutation in a Portuguese case[J].Gene.2014,538(2):288-291.
17 Wei Q,Zhu H,Qian X,et al.Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss[J].J Transl Med.2014,12:311.
18 Niu Z,Feng Y,Hu Z,et al.Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family[J].Int J Pediatr Otorhinolaryngol.2017,100:1-7.
19 Kobayashi M,Miyagawa M,Nishio SY,et al.WFS1 mutation screening in a large series of Japanese hearing loss patients:Massively parallel DNA sequencing-based analysis[J].PLoS One.2018,13(3):e0193359.
20 Gurtler N,Kim Y,Mhatre A,et al.Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1[J].J Mol Med(Berl).2005,83(7):553-560.
21 Stritt S,Nurden P,Turro E,et al.A gain-of-function variant in DI-APH1 causes dominant macrothrombocytopenia and hearing loss[J].Blood.2016,127(23):2903-2914.
22 Ganaha A,Kaname T,Shinjou A,et al.Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease[J].Am J Med Genet A.2017,173(10):2826-2830.
23 Neuhaus C,Lang-Roth R,Zimmermann U,et al.Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss(DFNA1)[J].Clin Genet.2017,91(6):892-901.
24 Snoeckx RL,Kremer H,Ensink RJ,et al.A novel locus for autosomal dominant non-syndromic hearing loss,DFNA31,maps to chromosome 6p21.3[J].J Med Genet.2004,41(1):11-13.
25 Moreno-Pelayo MA,Modamio-Hoybjor S,Mencia A,et al.DF-NA49,a novel locus for autosomal dominant non-syndromic hearing loss,maps proximal to DFNA7/DFNM1 region on chromosome 1q21-q23[J].J Med Genet.2003,40(11):832-836.
26 Gurtler N,Kim Y,Mhatre A,et al.DFNA54,a third locus for low-frequency hearing loss[J].J Mol Med(Berl).2004,82(11):775-780.
27 B?nsch D,Schmidt CM,Scheer P,et al.Ein neuer Genort für eine autosomal dominante,nichtsyndromale H?rst?rung(DF-NA57)kartiert auf Chromosom 19p13.2 undüberlappt mit DF-NB15[J].Hno.2008,56(2):177-182.
28 Starr A,Picton TW,Sininger Y,et al.Auditory neuropathy[J].Brain.1996,119(Pt 3):741-753.
29王秋菊,Starr A.听神经病:从发现到渐入精准[J].中华耳鼻咽喉头颈外科杂志.2018,53(3):161-171.Wang QJ,Starr A.Hereditary auditory neuropathies:stepping into precision management from the discovery[J].Chin J Otorhinolaryngol Head Neck Surg.2018,53(3):161-171.
30 Kim TB,Isaacson B,Sivakumaran TA,et al.A gene responsible for autosomal dominant auditory neuropathy(AUNA1)maps to13q14-21[J].J Med Genet.2004,41(11):872-876.
31王洪阳,王秋菊.目标区域捕获联合新一代测序技术在遗传性聋研究中的应用及发展前景[J].听力学及言语疾病杂志.2014,22(05):531-536.Wang HY,Wang QJ.Application and prospects of target region capture and next generation sequencing technology in inheritant deafness research.Journal of Audiology and Speech Pathology.2014,22(05):531-536.