近亲结婚所致一遗传性非综合征型耳聋家系的调查

耳聋是一种最常见的人类感觉系统缺陷, 在已发现的遗传性耳聋中,有70％的属于非综合征型听力缺损。据估计非综合征型遗传性耳聋基因总数在100个以上,目前已经确定了近80个非综合征型遗传性耳聋的遗传位点,其中23个基因已经被成功克隆。文章报道一遗传性非综合征型耳聋家系。该家系中存在2代近亲结婚,共2代13人出现聋哑症状。经遗传分析,该家系的遗传方式与常染色体显性或隐性遗传均不符合,提示此家系中的非综合征型遗传性耳聋可能为线粒体突变所致。     

线粒体DNA G7444A突变可能影响A1555G突变的表型表达

线粒体12S rRNA和tRNASer(UCN) 基因是导致非综合征型听力损失的两个突变热点区域。作者收集了1个母系遗传感音神经性聋家系, 该家系同时携带线粒体DNA (mtDNA) A1555G和G7444A突变。临床资料分析表明, 该家系包括药物致聋的耳聋外显率(所有耳聋患者/所有母系成员)为58%, 而非药物致聋的耳聋外显率(非药物性聋患者/所有母系成员)为25%, 明显高于其他携带A1555G突变的耳聋家系。先证者的线粒体全序列分析表明, 该线粒体基因组共有28个多态位点, 属于东亚人群B4c1单体型。在这些多态位点中, 除A1555G和G7444A突变外, 未发现其他有功能意义的突变。这表明mtDNA G7444A突变可能加重由A1555G突变造成的线粒体功能缺失, 从而增加耳聋的外显率。     

一个遗传五代的成骨不全症家系

成骨不全症又叫脆骨蓝色巩膜综合征,为 一组遗传性疾病。本症以蓝色巩膜、成骨不全 及耳聋为主要特点。我院在遗传咨询门诊发现 一家系,在5代人中有蓝色巩膜者22人,占家 族成员62.86外(22/35),现报道如下。     

线粒体tRNAThr G15927A突变可能影响耳聋相关的12S rRNA A1555G突变的表型表达

摘要: 对1个中国汉族耳聋家系进行了临床和分子遗传学特征分析。家系中听力下降的母系成员表现为程度不等、听力图形态不同的听力损害, 但同为双侧对称的感觉神经性耳聋。该家系耳聋外显率很高, 包括药物致聋的耳聋外显率为75%, 而非药物致聋的外显率为41.7%。对母系成员进行线粒体DNA(mtDNA)全序列扩增分析, 发现了耳聋相关12S rRNA A1555G同质性突变位点和多态性位点, 属于东亚人群B5b单体型。在这些变异位点中, mtDNA 15927位点的G-A碱基变化破坏tRNA^Thr反密码子结构上十分保守的C-G碱基对, 这可能加重由A1555G突变造成的线粒体功能缺陷。这表明tRNAThrG15927A突变可能增强携带12S rRNA A1555G的中国汉族耳聋家系的外显率和表现度。     

新生儿筛查发现的非综合征型耳聋病例及其家系进行GJB2基因全编码区变异分析

通过对温州地区新生儿听力筛查发现的遗传性非综合征型耳聋病例及其家系进行GJB2(gap junction beta 2)基因全编码区变异分析,寻找致聋GJB2基因突变,探讨GJB2基因复合变异的致聋性。该研究通过提取21个家系先证者及其57个家系成员的外周血基因组DNA,聚合酶链反应(polymerase chain reaction,PCR)扩增GJB2基因的全编码序列,扩增产物经限制性片段长度多态性(restriction fragment length polymorphism,RFLP)初步筛查235del C,然后对扩增产物进行DNA测序,并进一步对序列变异进行生物信息学分析。结果显示,21个非综合征型耳聋家系中,7个家系确诊是GJB2基因突变所致,GJB2致聋基因突变类型包括235del C纯合、299-300del AT+109GA复合杂合。还发现2个家系的GJB2基因变异可能致聋,分别为79GA+109GA+341AG复合杂合、79GA纯合+558GA杂合。但结果显示,79GA+341AG复合杂合或复合纯合、235del C+79GA复合杂合一般不足以致聋。以上结果表明,GJB2基因复合变异在非综合征型耳聋病例中常见。某些GJB2基因变异是否致聋具有明显遗传异质性。多态性变异的多重复合有时可能致聋。遗传背景和(或)环境因素可能参与GJB2基因变异的致聋性。     

GSDMDC家族基因功能研究进展

GSDMDC家族是近年来发现的一个全新的含有Gasdermin结构域的蛋白超家族,包括DFNA5、DFNA5L、GSDM、 GSDML 和 MLZE五个成员。研究表明GSDMDC家族可能与组织器官发育以及肿瘤,耳聋和脱发等遗传疾病相关,因而具有重要生理功能。其中,对该家族的DFNA5基因研究报道相对较多,它是常染色体显性非综合征性耳聋致病基因之一,并可能与黑色素瘤和乳腺癌相关。但对DFNA5基因在细胞和分子水平作用机制仍不清楚。对Gasdermin结构域的空间结构、特点、相互作用蛋白和生理功能也知之甚少。将来的研究将揭示此家族各成员的确切生理功能及其与疾病相关性。

     

先天性聋哑会遗传吗？

问：我妈妈是先天性聋哑人,爸爸是后天吃药所致的聋哑,其他家族成员都是正常人,我很健康,我爱人也很健康,他的家族没有遗传病史。我现在怀孕18周了,请问我的宝宝是否会有遗传的危险？ 答：先天性耳聋的发生率大约为每1 500 个新生儿中1人发病,主要为常染色体隐性遗传,占75%以上。非遗传性先天性耳聋约占20%。遗传性耳聋分为非综合征和综合征性两大类,分别占80%和20%左右,目前已明确的耳聋致病基因约50个。综合征性遗传性耳聋是一些综合征的伴随症状,如Alport综合征、 Vohwinkel综合征、Pendred综合征、Wolfram综合征、Stickler综合征、Waardenberg综合征, Usher 综合征等。此外,还有一类线粒体基因突变引起的耳聋如糖尿病性耳聋等。非遗传性耳聋可因先天性感染、孕妇代谢因素、服用药物等所引起。因此,按照你提供的家系分析,假定你母亲属于遗传性耳聋,且为常染色体隐性遗传,你现在没有发病,最多是携带者,你先生及其家族成员没有类似病史,你们所生子女不会发生遗传性耳聋。当然如果能明确你母亲的致病基因,通过基因检测可以知道你是否携带该致病基因。你父亲的药物性耳聋一般认为属于非遗传性耳聋,但不能排除存在易感基因的可能,应尽量避免使用同类导致耳聋的药物。     

常染色体显性遗传非综合征性耳聋致病基因定位研究

耳聋具有高度的遗传异质性, 迄今已定位了51个常染色体显性遗传非综合征型耳聋(autosomal dominant non-syndromic sensorineural hearing loss, DFNA)基因位点, 20个DFNA相关基因被克隆。文章收集了一个DFNA巨大家系, 家系中有血缘关系的家族成员共170人, 对73名家族成员进行了详细的病史调查、全身检查和耳科学检查, 提示39人有不同程度的迟发性感音神经性听力下降, 未见前庭及其他系统的异常。应用ABI公司382个常染色体微卫星多态标记进行全基因组扫描连锁分析, 将该家系致聋基因定位于14q12-13处D14S1021-D14S70之间约7.6 cM (3.18 Mb)的区域, 最大LOD值为6.69 (D14S1040), 与已知DFNA9位点有4.7 cM (2.57 Mb)的重叠区, DFNA9致病基因COCH位于重叠区域内。下一步拟进行COCH基因的突变筛查, 以揭示该家系耳聋的分子致病机制。     

常染色体显性遗传非综合征型耳聋致病基因定位研究

耳聋具有高度的遗传异质性, 迄今已定位了51个常染色体显性遗传非综合征型耳聋(autosomal dominant non-syndromic sensorineural hearing loss, DFNA)基因位点, 20个DFNA相关基因被克隆.文章收集了一个DFNA巨大家系, 家系中有血缘关系的家族成员共170人, 对73名家族成员进行了详细的病史调查、全身检查和耳科学检查, 提示39人有不同程度的迟发性感音神经性听力下降, 未见前庭及其他系统的异常.应用ABI公司382个常染色体微卫星多态标记进行全基因组扫描连锁分析, 将该家系致聋基因定位于14q12-13处D14S1021-D14S70之间约7.6 cM (3.18 Mb)的区域, 最大LOD值为6.69 (D14S1040), 与已知DFNA9位点有4.7 cM (2.57 Mb)的重叠区, DFNA9致病基因COCH位于重叠区域内.下一步拟进行COCH基因的突变筛查, 以揭示该家系耳聋的分子致病机制.     

一例遗传性肾炎家系

遗传性肾炎于1874年首先由Samelsohu提出。1902年Guthrie对本病进一步作了描述。25年后,Alport注意到本病的家族成员中肾炎和耳聋的关系,称本病为A1port综合征。1951年Fanconi等发现本病并发眼病,且多发生于青少年,故称青少年肾病眼炎。在临床上由于本病常伴有耳疾(耳聋、中耳炎等)和眼疾(近视、白内障、视网膜炎或眼球震颤等),故也称耳、眼、肾综合征。但一般多称遗传性肾炎。本病全世界已报道有50例以上。近年来,我国也陆续有所报道。 本文报告一例通过直接调查获得的遗传性肾炎家系,共4代9人。至于家     

A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred

DFNA23, a novel locus for autosomal dominant nonsyndromic hearing loss, was identified in a Swiss German kindred. DNA samples were obtained from 22 family members in three generations: 10 with hearing impairment caused by the DFNA23 locus, 8 unaffected offspring, and 4 spouses of hearing-impaired pedigree members. In this kindred, the hearing-impaired family members have prelingual bilateral symmetrical hearing loss. All audiograms from hearing-impaired individuals displayed sloping curves, with hearing ability ranging from normal hearing to mild hearing loss in low frequencies, normal hearing to profound hearing loss in mid frequencies, and moderate to profound hearing loss in high frequencies. A conductive component existed for 50% of the hearing-impaired family members. The majority of the hearing-impaired family members did not display progression of hearing loss. The DFNA23 locus maps to 14q21-q22. Linkage analysis was carried out under a fully penetrant autosomal dominant mode of inheritance with no phenocopies. A maximum multipoint LOD score of 5.1 occurred at Marker D14S290. The 3.0-LOD unit support interval is 9.4 cM and ranged from marker D14S980 to marker D14S1046.     

Maternally inherited non-syndromic hearing loss associated with mitochondrial 12S rRNA A827G mutation in a Chinese family

We explored the clinical and molecular characterization of a Chinese family with non-syndromic hearing impairment. Clinical evaluations revealed a possible maternal inheritance pattern, and showed an extremely similar phenotype of hearing loss including the age of onset, severity, and audiometric configuration. Sequence analysis of the mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, which was absent in other family members and 40 Chinese controls. This mutation has previously been reported sporadically in a few individuals with aminoglycoside-induced and non-syndromic hearing loss. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly evolutionarily conserved in mammals. The occurrence of the A827G mutation in these genetically unrelated subjects strongly suggests that this mutation is involved in the pathogenesis of hearing impairment. However, incomplete penetrance of hearing loss indicates that the A827G mutation alone is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression, even though aminoglycosides and GJB2 gene may not contribute to the penetrance of the A827G mutation in this Chinese family. In contrast with the variable phenotype of hearing loss associated with other mitochondrial mutations, all of the patients in our family exhibited strikingly similar clinical features. This discrepancy likely reflects the difference of genetic backgrounds between this pedigree and others.     

Moderate hearing loss and pseudodominant inheritance due to L90P/35delG mutations in the GJB2 (connexin 26) gene

Mutations in the GJB2 (connexin 26-Cx26) gene are responsible for 20-50% of cases with prelingual non-syndromic deafness in a large part of the world including Turkey. Although most of the cases with Cx26 deafness have a recessive mode of inheritance, a small group of families demonstrated dominant or pseudodominant inheritance. In this report we present a Turkish family in which the proband had congenital profound deafness and was found to be homozygous for the 35delG mutation, whereas the father and a paternal uncle who had milder, late-onset sensorineural hearing loss had compound heterozygous 35delG and L90P mutations. This family and previous reports with the L90P mutation demonstrate that the hearing loss associated with the L90P/35delG genotype is consistently milder than that of 35delG homozygotes. GJB2 gene screening should be considered in families with seemingly dominant inheritance and late-onset moderate hearing loss.     

The study of gene GJB2/DFNB1 causing deafness in humans by linkage analysis from district Peshawar

Families with at least 2 or more individuals having hereditary hearing loss were enrolled from different areas of Khyber Pakhtoonkhwa, mainly from district Peshawar. Detailed history was taken from each family to minimize the presence of other abnormalities and environmental causes for deafness. Families were questioned about skin pigmentation, hair pigmentation, and problems relating to balance, vision, night blindness, thyroid, kidneys, heart, and infectious diseases like meningitis, antibiotic usage, injury, and typhoid. The pedigree structures were based upon interviews with multiple family members, and pedigrees of the enrolled families were drawn using Cyrillic program (version 2.1). All families showed recessive mode of inheritance. I studied 8 families of these 10. For linkage analyses, studies for DFNB1 locus, 3 STR markers (D13S175, D13S292, and D13S787) were genotyped using polyacrylamide gel electrophoresis (PAGE) and haplotypes were constructed to determined, linkage with DFNB1 locus. From a total of 8 families, a single family-10 showed linkage to DFNB1 locus.     

The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family

We report here the clinical, genetic and molecular characterization of a large Han Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. The penetrance of hearing loss (affected matrilineal relatives/total matrilineal relatives) in this pedigree was 53%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in this pedigree was 42%. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA A1555G mutation and other 35 variants belonging to Eastern Asian haplogroup D4. Of these, the V313I (G11696A) mutation in ND4 was associated with vision loss. However, the extremely low penetrance of visual loss, and the mild biochemical defect and the presence of one/167 Chinese controls indicted that the G11696A mutation is itself not sufficient to produce a clinical phenotype. Thus, the G11696A mutation may act in synergy with the primary deafness-associated 12S rRNA A1555G mutation in this Chinese family, thereby increasing the penetrance and expressivity of hearing loss in this Chinese pedigree.     

Analysis of the inheritance pattern of a Chinese family with phaeochromocytomas through whole exome sequencing

Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare, catecholamine-producing tumors. Most familial PCC/PGLs have been detected to be autosomal dominantly inherited. However, this study was undertaken in a family with PCCs to determine candidate genes in a dominant or recessive inheritance pattern. After excluding mutations in ten PCC/PGL susceptibility genes by Sanger sequencing, we used whole exome sequencing for screening on the four family members to discover novel candidate genes associated with PCCs. Based on the inexistence of non-synonymous mutations or indels in the ten known genes and the structure of this pedigree, 3 damaging loci with dominant inheritance pattern, and 5 damaging loci with recessive homozygous inheritance pattern and 6 damaging genes with compound heterozygous inheritance pattern were narrowed down to indicate the association with PCCs. According to the Gene Ontology (GO) category analysis on the combined results, cell adhesion showed the most significant enrichment.     

Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

Comprehensive genetic testing has the potential to become the standard of care for individuals with hearing loss. In this study, we investigated the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL) in a Turkish cohort including individuals with cochlear implant, who had a pedigree suggestive of an autosomal recessive inheritance. A workflow including prescreening of GJB2 and a targeted next generation sequencing panel (Illumına TruSight^TM Exome) covering 2761 genes that we briefly called as mendelian exome sequencing was used. This panel includes 102 deafness genes and a number of genes causing Mendelian disorders. Using this approach, we identified causative variants in 21 of 29 families. Three different GJB2 variants were present in seven families. Remaining 14 families had 15 different variants in other known NSHL genes (MYO7A, MYO15A, MARVELD2, TMIE, DFNB31, LOXHD1, GPSM2, TMC1, USH1G, CDH23). Of these variants, eight are novel. Mutation detection rate of our workflow is 72.4%, confirming the usefulness of targeted sequencing approach in NSHL.     

Mitochondrial tRNAGlu 14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Hah Chinese family

Mutations in mitochondrial 12S rRNA gene are one of the most important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we report the characterization of one Han Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing loss.This Chinese family carrying the 12S rRNA A1555G mutation exhibited high penetrance and expressivity of hearing impairment. In particular, penetrances of hearing loss in this family pedigree were 43.8% and 25%, respectively, when aminoglycoside-induced heating loss was included or excluded. Mutational analysis of entire mitochondrial genomes in this family showed the homoplasmic A1555G mutation and a set of variants belonging to haplogroup Y2. Of these, the A14693G variant occurred at the extremely conserved nucleotide (conventional position 54) of the TψC-loop of tRNAGlu and was absent in 156 Chinese controls. Nucleotides at position 54 of tRNAs are often modified, thereby contributing to the structural formation and stabilization of functional tRNAs. Thus, the structural alteration of tRNA by the A14693G variant may lead to a failure in tRNA metabolism and impair mitochondrial protein synthesis, thereby worsening mitochondrial dysfunctions altered by the A1555G mutation. Therefore, the tRNAalu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated AI555G mutation in this Chinese pedigree.     

一个非综合征性耳聋家系致病基因的研究

非综合征性耳聋(nonsyndromic hearing impairment, NSHI)是一种十分常见的人类神经系统疾病, 约有1/1000的新生儿患有语前聋。GJB2基因编码间隙连接蛋白Cx26, 是最常见的NSHI致病基因, 大约50%的常染色体隐性遗传NSHI是由GJB2基因突变引起的。在本研究中, 收集了江苏省一个复杂的非综合征性耳聋家系, 并对其进行了分子遗传学研究。对所有已知常染色体隐性遗传的NSHI致病基因, 选用其侧翼的微卫星标记进行连锁分析, 发现该家系的致病基因与D13S175连锁。对GJB2基因进行整个编码区域的测序, 发现235碱基处发生了碱基C的纯合缺失, 这一突变可能是该家系中绝大多数患者致病的遗传基础。