Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

聽力障礙是最常見的出生缺陷之一，大約每一千個新生兒中就有三個表現為聽力障礙。世界衛生組織的一份最新報告顯示，世界範圍內有三億六千萬人有大於或等於30 分貝聽閾值的聽損。在中國，根據第二次國家殘疾調查數據估計有兩千萬人群已經診斷為聽力障礙。約佔中國總人口的百分之一點五。其中有十一萬伍仟小於七歲的兒童診斷為重度失聰， 且每年至少有三萬名新生兒有聽力障礙。 / 遺傳性耳聾可根據臨床表現診斷。然而導致耳聾的遺傳背景卻千差萬別。遺傳因素約佔學語前性耳聾的百分之五十。明確導致耳聾的遺傳性致病因素有助於解釋疾病的發生發展，臨床診療決策，針對病人及家屬有效的遺傳咨詢。然而在臨床上開展針對遺傳性耳聾的分子診斷確非易事。 / 根據文獻報導不同種族耳聾患者尤其獨特的熱點突變類型。了解中國人群的突變種類和人群攜帶率有助於開展耳聾的分子診斷。經過針對中國耳聾患者文獻報導的查詢，我們發現15 個常見突變。並在中國新生兒人群中採用SNaPshot 方法鑑定這15 個突變的基因型。由於Sanger 測序方法所能檢測該方法所能檢測的基因型有限，考慮到遺傳性耳聾的致病基因眾多，我們將液相捕獲和二代測序相結合來實現高通量篩查。針對二百多個耳聾相關基因設計捕獲探針，雜交捕穫後同時進行二代測序。針對該流程自設的生物信息分析方法可有效定位變異位點，且sanger 測序驗證率高。我們亦同時設計了NimbleGen 和Agilent 兩種平台的液相捕獲探針文庫。最終在七名患者中的兩名找到可能與耳聾相關的遺傳突變。 / 伴隨著分子診斷對耳聾患者的廣泛應用，產前診斷需求亦有增加。傳統產前診斷需要有創操作獲取胎兒組織。這些操作可能對胎兒不利從而導致流產。我們將母親血漿DNA 分析胎兒基因型的無創方法应用在一例遺傳性耳聾的產前診斷。胎兒經過分析為致病突變攜帶者。該結果與孕中期有創產前基因檢查結果一致。 / 總而言之，該論文中所總結的耳聾熱點突變的中國人群攜帶率有助於耳聾患者的風險評估和遺傳咨詢。目標區域富集結合二代測序以及無創單倍體分型的方法建立都將增強遺傳性耳聾的基因診斷的應用。 / Hearing loss is one of the most common birth defects, with a prevalence rate of approximately 3 per 1000 neonates. In the latest WHO report, 360 million people worldwide have hearing loss at least greater than 30dB. In China, based on the data of the Second China National Sample Survey on Disability, it was estimated that 20 million people were diagnosed with hearing disability. This accounts for 1.5% of the total Chinese population, and represents 115 000 children under the age of 7 years with severe-to-profound deafness and 30 000 newborns (~0.15%) each year with hearing impairment. / Hereditary hearing loss is due to genetic defects. Therefore establishing a genetic diagnosis for hereditary hearing loss is favorable for explanation of the disease, determination of clinical management, and to offer appropriate genetic counseling for patients and their family members. It has a well-recognized phenotype which is relatively easy to be diagnosed clinically. Nonetheless, genetic causes contributing to hearing impairment are unparalleled heterogeneous. Implementing genetic diagnosis in clinical practice for hereditary hearing loss is challenging. / It has been reported that different ethnic groups show a unique spectrum of common mutations of hearing loss genes. Understanding the spectrum and carrier frequency of common mutations particularly in the Chinese population could facilitate the molecular diagnosis of hearing loss. According to common mutations extracted from the literatures regarding hearing loss patients, we studied the carrier frequency of 15 common mutations in GJB2, SLC26A4 and the mitochondrial genome by the SNapShot method. This is the first epidemiological study of nonsyndromic hearing loss in Chinese that reveals high carrier frequencies (one per 6.3 newborns) of 15 common mutations in newborns. / Considering the limitation of mutations screened by Sanger sequencing, we developed the solution-based capture system with massively parallel sequencing (MPS) to target more than 252 genes related with hearing loss. An in-house bioinfomatic analysis pipeline was constructed to identify candidate variants with a high validation rate. We designed both Agilent SureSelect and NimbleGen SeqCap target enrichment platforms and adopted them for the mutation discovery of hearing loss genes in unrelated Chinese families with nonsyndromic hearing loss. Our targeted genome enrichment (TGE) MPS approach identified an additional 28% (2 out of 7) of unrelated Chinese families carrying novel mutations. / As more hearing loss patients receive a genetic diagnosis, there will be a foreseeable growing demand for prenatal diagnosis. Standard prenatal testing requires an invasive procedure to obtain a fetal sample, which has the risk of fetal loss. Therefore we explored the application of a noninvasive method using cell free fetal DNA in a family with a GJB2 mutation. Using haplotype analysis of a 1.1 Mb flanking region around GJB2, we successfully recovered the fetal haplotype and deduced that the fetus inherited the paternal mutant allele and maternal wide-type allele. / In summary, our carrier frequency data aid in effective risk assessment and genetic counseling for hearing loss patients in the Chinese population. The newly established target genome enrichment MPS method and noninvasive haplotype approach enhanced the success of genetic diagnosis of hereditary hearing loss. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Cao, Ye. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 116-130). / Abstracts also in Chinese.