The amazing advances brought forward by the completion of the Human Genome Project, new sequencing technologies and new methodologies to extract specific fragments of genomic DNA (gDNA), have now made it possible to sequence the """"""""exome"""""""" in an individual patient in a relatively short time-frame (whole exome sequencing, WES). The Core PI and Co-PI of are thoroughly expert in the design and implementation of next-generation sequencing (NGS) experiments, and will establish and operate the NGS Core B to generate WES data across each ofthe proposed Projects, involving human, mouse and zebrafish. It has long been appreciated that the vast majority of alleles with strong effect are located in the exome, which constitutes just 1% of most vertebrate genomes. The methodologies to capture and sequence the exome in humans was the first to emerge and is transforming the way scientists approach genetic disease. Methodologies to capture and sequence the mouse and zebrafish exomes will be available shortly. In this Core, we will bring these technologies to bear on structural brain diseases (SBDs) across the evolutionary spectrum. We have been successful at generating WES data that produces 95% target bases at >10X coverage. For dominant disease, the ability to systematically identify heterozygous variants is limited by this coverage, but for recessive disease, this hurdle is easily overcome. Because recessive disease due to homozygous mutations in humans, mouse and zebrafish is the focus of this application, we will be extraordinarily well-powered to identify causative mutations in these species using this approach. An important aspect of Core B is the close ties that will develop not just to the Scientific Projects but also with Core C (Bioinformatics Core) and Core A (Administrative Core). Core C will develop and utilize new software that is specifically devised for identifying homozygous potentially deleterious sequence variants (PDSVs) in the data from Core B. Core A will support the technological infrastructure of both Core B and Core C. Projects I, II and III will be well-positioned to uncover new mechanisms of SBDs, and translate these into new discoveries about underlying mechanisms.
Almost 5% of all births in the US, and an even higher percent in other world populations, are affected by birth defects, and of these, structural brain defects make a major contribution. We will develop and optimize methodology to increase sensitivity and specificity of detecting genetic causes, which can be translated into improved diagnostic strategies for the population in general.
|Marin-Valencia, Isaac; Novarino, Gaia; Johansen, Anide et al. (2018) A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. J Med Genet 55:48-54|
|Schaffer, Ashleigh E; Breuss, Martin W; Caglayan, Ahmet Okay et al. (2018) Biallelic loss of human CTNNA2, encoding ?N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. Nat Genet 50:1093-1101|
|Makrythanasis, Periklis; Maroofian, Reza; Stray-Pedersen, Asbjørg et al. (2018) Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet 26:330-339|
|De Mori, Roberta; Romani, Marta; D'Arrigo, Stefano et al. (2017) Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects. Am J Hum Genet 101:552-563|
|Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450|
|Friedman, Jennifer; Feigenbaum, Annette; Chuang, Nathaniel et al. (2017) Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89:2297-2298|
|Koizumi, Hiroyuki; Fujioka, Hiromi; Togashi, Kazuya et al. (2017) DCLK1 phosphorylates the microtubule-associated protein MAP7D1 to promote axon elongation in cortical neurons. Dev Neurobiol 77:493-510|
|McConnell, Michael J; Moran, John V; Abyzov, Alexej et al. (2017) Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science 356:|
|Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464|
|Breuss, Martin W; Nguyen, Thai; Srivatsan, Anjana et al. (2017) Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability. Hum Mol Genet 26:258-269|
Showing the most recent 10 out of 70 publications