Precision Health and Deafness: Optimizing Genetic Diagnosis
Başlık:
Precision Health and Deafness: Optimizing Genetic Diagnosis
Yazar:
Sloan-Heggen, Christina Marie, author.
ISBN:
9780438151253
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (191 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Richard JH Smith Committee members: Christopher A. Ahern; Michael G. Anderson; Amy Lee; Todd E. Scheetz; John A. Wemmie.
Özet:
Deafness is the most common sensory deficit in humans. In the United States 1--2 in a thousand babies is born with significant deafness, well over half of which is hereditary. Providing a patient and their family with a genetic diagnosis is the ultimate form of precision health and medicine; it can provide education, impact medical testing and treatment, provide peace of mind, and someday will be the key to providing gene specific therapies. Historically, providing this diagnosis was difficult, expensive, and time consuming due to the extreme clinical and genetic heterogeneity of non-syndromic hearing loss (NSHL).
Targeted genomic enrichment and massively parallel sequencing (TGE+MPS) have revolutionized the field of precision health and medicine, allowing for comprehensive genetic diagnosis of many complicated conditions, including NSHL. To take advantage of this advance in technology, the OtoSCOPE RTM platform was created, targeting all known deafness-causing genes and creating the first comprehensive genetic test for this condition.
With the implementation of OtoSCOPERTM we aspire to accomplish two aims: providing comprehensive genetic diagnosis for patients all over the world and characterizing the full spectrum of hereditary hearing loss. The goal of my thesis work has been to use OtoSCOPERTM to better understand the landscape of NSHL in multiple populations and to use this knowledge to further optimize it to be the most effective and tailored diagnostic tool possible for individuals with deafness. In order to achieve these goals, we investigated a few unique populations. We first evaluated the effectiveness of diagnosis of OtoSCOPERTM on two preselected cohorts of 302 Iranian and 9 Cameroonian probands with autosomal recessive NSHL (ARNSHL). We can now better define the frequent causes of NSHL in Iranians with a high degree of inbreeding, and begin to understand the spectrum of deafness in Sub-Saharan Africa that has previously been underutilized. Next we sought to determine the spectrum of hearing loss within a clinical cohort in the United States by evaluating 1119 sequentially accrued probands for whom the OtoSCOPERTM panel was ordered as a diagnostic test. This analysis allowed us to determine the overall diagnostic success of OtoSCOPE RTM (39%), the most common genes responsible for NSHL, the overall breadth of genes that can be identified within a cohort like this (49 genes), and patient characteristics which impact the likelihood of providing a positive diagnosis. This study permitted us to recommend use of OtoSCOPERTM or other TGE+MPS diagnostic tools early in the diagnostic process of a patient with NSHL.
Finally, we interrogated the contribution of syndromic forms of deafness which may actually manifest as NSHL (NSHL mimics) within two deafness cohorts. We performed a retrospective chart review of 14 families with syndromic deafness seen by the Genetic-Eye-Ear Clinics to determine which methods are the most efficient and effective at providing an accurate diagnosis through the combination of collaborative clinical and molecular genetic diagnostic tools. We also performed a secondary analysis of 2384 sequentially accrued probands clinically evaluated with OtoSCOPERTM, specifically evaluating the impact of panel versioning and inclusion of additional NSHL mimics. We recommend use of OtoSCOPERTM as a diagnostic tool to most patients with apparent NSHL, and utilize an automatic positive feedback loop to ensure the most comprehensive and accurate diagnosis possible.
All of these studies have lead to the better understanding of the genes and variants that cause NSHL and its mimics, providing a more accurate genetic diagnosis, which is prerequisite to a future of targeted genetic therapies.
Notlar:
School code: 0096
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(687762.1) | 687762-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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