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Liu, Qin

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Liu

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Qin

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Liu, Qin
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    Panel-based Genetic Diagnostic Testing for Inherited Eye Diseases is Highly Accurate and Reproducible and More Sensitive for Variant Detection Than Exome Sequencing
    (2015) Consugar, Mark B.; Navarro-Gomez, Daniel; Place, Emily; Bujakowska, Kinga; Sousa, Maria E.; Fonseca-Kelly, Zoë D.; Taub, Daniel G.; Janessian, Maria; Wang, Dan Yi; Au, Elizabeth D.; Sims, Katherine B.; Sweetser, David; Fulton, Anne; Liu, Qin; Wiggs, Janey; Gai, Xiaowu; Pierce, Eric
    Purpose Next-generation sequencing (NGS) based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques have not been fully defined with regard to test accuracy and reproducibility. Methods: We developed a targeted enrichment and NGS approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy and glaucoma. In preparation for providing this Genetic Eye Disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, reproducibility as well as the clinical sensitivity of the test. Results: The GEDi test is highly reproducible and accurate, with sensitivity and specificity for single nucleotide variant detection of 97.9% and 100%, respectively. The sensitivity for variant detection was notably better than the 88.3% achieved by whole exome sequencing (WES) using the same metrics, due to better coverage of targeted genes in the GEDi test compared to commercially available exome capture sets. Prospective testing of 192 patients with IRDs indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. Conclusion: The data suggest that based on quantified performance metrics, selective targeted enrichment is preferable to WES for genetic diagnostic testing.
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    NMNAT1 Mutations Cause Leber Congenital Amaurosis
    (Nature Publishing Group, 2012) Falk, Marni J; Nakamaru-Ogiso, Eiko; Kannabiran, Chitra; Chakarova, Christina; Audo, Isabelle; Mackay, Donna S; Zeitz, Christina; Borman, Arundhati Dev; Shukla, Rachna; Palavalli, Lakshmi; Mohand-Said, Saddek; Waseem, Naushin H; Jalali, Subhadra; Perin, Juan C; Ostrovsky, Julian; Xiao, Rui; Bhattacharya, Shomi S; Webster, Andrew R; Sahel, José-Alain; Moore, Anthony T; Gai, Xiaowu; Zhang, Qi; Kelly, Zoe; Staniszewska, Magdalena; Place, Emily; Consugar, Mark Bryant; Berson, Eliot L.; Liu, Qin; Pierce, Eric
    Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss. Two-thirds of LCA cases are caused by mutations in 17 known disease genes (RetNet Retinal Information Network). Using exome sequencing, we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 as likely disease-causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in their kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide \((NAD^+)\) biosynthesis. Functional studies showed the p.Val9Met mutation decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated LCA families identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA.
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    Publication
    Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses
    (Springer Science and Business Media LLC, 2020-01-14) Levy, Jonathan; Yeh, Wei Hsi; Pendse, Nachiket; Davis, Jessie; Hennessey, Erin; Butcher, Rossano; Luke, Koblan; Comander, Jason; Liu, Qin; Liu, David
    Base editors are widely used engineered proteins that introduce targeted point mutations into DNA without creating double-stranded DNA breaks. The application of base editors to study and treat genetic diseases is dependent on their in vivo delivery into relevant cell types. Delivery by adeno-associated virus (AAV), a clinically validated delivery method, poses special challenges because the size of base editors exceeds the AAV packaging limit. Here we describe the development and application of in vivo delivery methods for both cytosine base editors (CBEs) and adenine base editors (ABEs). Dual AAVs each provide one half of the editor and trans-splicing inteins reconstitute full base editor activity, circumventing the AAV packaging limit. We optimized each AAV component to greatly improve editing efficiency. The resulting AAVs enable in vivo base editing for the first time in mouse brain, retina, and heart, as well as the most efficient base editing to date in muscle and liver, with therapeutically relevant efficiencies at viral dosages known to be tolerated in humans. A single intravenous injection of split CBE in PHP.eB AAV resulted in editing of up to 59% of unsorted mouse cortical tissue. Intravenous injection of split CBE or ABE in AAV9 mediated up to 38%, 20%, and 9% base editing in unsorted mouse liver, heart, and skeletal muscle, respectively. Subretinal and intracerebroventricular injections of split CBE and ABE in Anc80, PHP.B/PHP.eB, and AAV9 viruses mediated mouse retina and brain editing in up to 38% and 50% of unsorted cells, respectively. We applied this system to directly correct in mouse brain tissue a mutation that causes the neurodegenerative ataxia Niemann-Pick disease type C (NPC), slowing neurodegeneration and increasing lifespan consistent with expectations based on mosaic NPC mice. These findings establish a broadly useful AAV platform for the efficient introduction of targeted point mutations into multiple tissues of therapeutic interest for which in vivo base editing has not been previously reported.