@article {722, title = {Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.}, journal = {Front Genet}, volume = {10}, year = {2019}, month = {2019}, pages = {611}, abstract = {

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

}, issn = {1664-8021}, doi = {10.3389/fgene.2019.00611}, author = {Nellaker, Christoffer and Alkuraya, Fowzan S and Baynam, Gareth and Bernier, Raphael A and Bernier, Francois P J and Boulanger, Vanessa and Brudno, Michael and Brunner, Han G and Clayton-Smith, Jill and Cogn{\'e}, Benjamin and Dawkins, Hugh J S and deVries, Bert B A and Douzgou, Sofia and Dudding-Byth, Tracy and Eichler, Evan E and Ferlaino, Michael and Fieggen, Karen and Firth, Helen V and FitzPatrick, David R and Gration, Dylan and Groza, Tudor and Haendel, Melissa and Hallowell, Nina and Hamosh, Ada and Hehir-Kwa, Jayne and Hitz, Marc-Phillip and Hughes, Mark and Kini, Usha and Kleefstra, Tjitske and Kooy, R Frank and Krawitz, Peter and K{\"u}ry, S{\'e}bastien and Lees, Melissa and Lyon, Gholson J and Lyonnet, Stanislas and Marcadier, Julien L and Meyn, Stephen and Moslerov{\'a}, Veronika and Politei, Juan M and Poulton, Cathryn C and Raymond, F Lucy and Reijnders, Margot R F and Robinson, Peter N and Romano, Corrado and Rose, Catherine M and Sainsbury, David C G and Schofield, Lyn and Sutton, Vernon R and Turnovec, Marek and Van Dijck, Anke and Van Esch, Hilde and Wilkie, Andrew O M} } @article {618, title = {Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 08}, pages = {1126-1138}, abstract = {

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

}, issn = {1098-1004}, doi = {10.1002/humu.23557}, author = {Kumar, Raman and Gardner, Alison and Homan, Claire C and Douglas, Evelyn and Mefford, Heather and Wieczorek, Dagmar and L{\"u}decke, Hermann-Josef and Stark, Zornitza and Sadedin, Simon and Nowak, Catherine Bearce and Douglas, Jessica and Parsons, Gretchen and Mark, Paul and Loidi, Lourdes and Herman, Gail E and Mihalic Mosher, Theresa and Gillespie, Meredith K and Brady, Lauren and Tarnopolsky, Mark and Madrigal, Irene and Eiris, Jes{\'u}s and Dom{\`e}nech Salgado, Laura and Rabionet, Raquel and Strom, Tim M and Ishihara, Naoko and Inagaki, Hidehito and Kurahashi, Hiroki and Dudding-Byth, Tracy and Palmer, Elizabeth E and Field, Michael and Gecz, Jozef} } @article {65, title = {Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {1001-1010}, abstract = {

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein~subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p~=~7.1~{\texttimes} 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.011}, author = {Petrovski, Slav{\'e} and K{\"u}ry, S{\'e}bastien and Myers, Candace T and Anyane-Yeboa, Kwame and Cogn{\'e}, Benjamin and Bialer, Martin and Xia, Fan and Hemati, Parisa and Riviello, James and Mehaffey, Michele and Besnard, Thomas and Becraft, Emily and Wadley, Alexandrea and Politi, Anya Revah and Colombo, Sophie and Zhu, Xiaolin and Ren, Zhong and Andrews, Ian and Dudding-Byth, Tracy and Schneider, Amy L and Wallace, Geoffrey and Rosen, Aaron B I and Schelley, Susan and Enns, Gregory M and Corre, Pierre and Dalton, Joline and Mercier, Sandra and Latypova, X{\'e}nia and Schmitt, S{\'e}bastien and Guzman, Edwin and Moore, Christine and Bier, Louise and Heinzen, Erin L and Karachunski, Peter and Shur, Natasha and Grebe, Theresa and Basinger, Alice and Nguyen, Joanne M and B{\'e}zieau, St{\'e}phane and Wierenga, Klaas and Bernstein, Jonathan A and Scheffer, Ingrid E and Rosenfeld, Jill A and Mefford, Heather C and Isidor, Bertrand and Goldstein, David B} }