Genetics and Genomics Commons^™

Cas9/Nickase-Induced Allelic Conversion By Homologous Chromosome-Templated Repair In, Sitara Roy, Sara Sanz Juste, Marketta Sneider, Ankush Auradkar, Carissa Klanseck, Zhiqian Li, Alison Henrique Ferreira Julio, Victor Lopez Del Amo, Ethan Bier, Annabel Guichard

Journal Articles

Repair of double-strand breaks (DSBs) in somatic cells is primarily accomplished by error-prone nonhomologous end joining and less frequently by precise homology-directed repair preferentially using the sister chromatid as a template. Here, a

A Nickase Cas9 Gene-Drive System Promotes Super-Mendelian Inheritance In Drosophila, Víctor López Del Amo, Sara Sanz Juste, Valentino M Gantz

Journal Articles

CRISPR-based gene-drives have been proposed for managing insect populations, including disease-transmitting mosquitoes, due to their ability to bias their inheritance toward super-Mendelian rates (>50%). Current technologies use a Cas9 that introduces DNA double-strand breaks into the opposing wild-type allele to replace it with a copy of the gene-drive allele via DNA homology-directed repair. However, the use of different Cas9 versions is unexplored, and alternative approaches could increase the available toolkit for gene-drive designs. Here, we report a gene-drive that relies on Cas9 nickases that generate staggered paired nicks in DNA to propagate the engineered gene-drive cassette. We show that …

Elucidating The Clinical Spectrum And Molecular Basis Of Hyal2 Deficiency, James Fasham, Siying Lin, Promita Ghosh, Francesca Clementina Radio, Emily G Farrow, Isabelle Thiffault, Jennifer Kussman, Dihong Zhou, Rick Hemming, Kenneth Zahka, Barry A Chioza, Lettie E Rawlins, Olivia K Wenger, Adam C Gunning, Simone Pizzi, Roberta Onesimo, Giuseppe Zampino, Emily Barker, Natasha Osawa, Megan Christine Rodriguez, Teresa M Neuhann, Elaine H Zackai, Beth Keena, Jenina Capasso, Alex V Levin, Elizabeth Bhoj, Dong Li, Hakon Hakonarson, Ingrid M Wentzensen, Adam Jackson, Kate E Chandler, Zeynep H Coban-Akdemir, Jennifer E Posey, Siddharth Banka, James R Lupski, Sarah E Sheppard, Marco Tartaglia, Barbara Triggs-Raine, Andrew H Crosby, Emma L Baple

Journal Articles

PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.

METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants.

RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and …

Absent B Cells, Agammaglobulinemia, And Hypertrophic Cardiomyopathy In Folliculin-Interacting Protein 1 Deficiency, Francesco Saettini, Cecilia Poli, Jaime Vengoechea, Sonia Bonanomi, Julio C Orellana, Grazia Fazio, Fred H Rodriguez, Loreani P Noguera, Claire Booth, Valentina Jarur-Chamy, Marissa Shams, Maria Iascone, Maja Vukic, Serena Gasperini, Manuel Quadri, Amairelys Barroeta Seijas, Elizabeth Rivers, Mario Mauri, Raffaele Badolato, Gianni Cazzaniga, Cristina Bugarin, Giuseppe Gaipa, Wilma G M Kroes, Daniele Moratto, Monique M Van Oostaijen-Ten Dam, Frank Baas, Silvère Van Der Maarel, Rocco Piazza, Zeynep H Coban-Akdemir, James R Lupski, Bo Yuan, Ivan K Chinn, Lucia Daxinger, Andrea Biondi

Journal Articles

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy …

Unraveling The Functional Role Of The Orphan Solute Carrier, Slc22a24 In The Transport Of Steroid Conjugates Through Metabolomic And Genome-Wide Association Studies, Sook Wah Yee, Adrian Stecula, Huan-Chieh Chien, Ling Zou, Elena V Feofanova, Marjolein Van Borselen, Kit Wun Kathy Cheung, Noha A Yousri, Karsten Suhre, Jason M Kinchen, Eric Boerwinkle, Roshanak Irannejad, Bing Yu, Kathleen M Giacomini

Journal Articles

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value