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35 results on '"Costain, G. A."'

1. P305: Evaluation of the feasibility, diagnostic yield, and utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): An international pilot study

Author: Yan Liang, NS, Costain, G, D'Gama, A, McTague, A, Howell, K, Chau, V, Mulhern, S, Poduri, A, Scheffer, I, Sheidley, B, Curtis, M, Higginbotham, E, Khan, T, McRae, L, Wiltrout, K, Hayeems, R, Jain, P, Lunke, S, Marshall, C, Chitty, L, Rockowitz, S, Stark, Z, White, S, Yan Liang, NS, Costain, G, D'Gama, A, McTague, A, Howell, K, Chau, V, Mulhern, S, Poduri, A, Scheffer, I, Sheidley, B, Curtis, M, Higginbotham, E, Khan, T, McRae, L, Wiltrout, K, Hayeems, R, Jain, P, Lunke, S, Marshall, C, Chitty, L, Rockowitz, S, Stark, Z, and White, S
Published: 2024

2. A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods.

Author: Oh, RY, AlMail, A, Cheerie, D, Guirguis, G, Hou, H, Yuki, KE, Haque, B, Thiruvahindrapuram, B, Marshall, CR, Mendoza-Londono, R, Shlien, A, Kyriakopoulou, LG, Walker, S, Dowling, JJ, Wilson, MD, Costain, G, Oh, RY, AlMail, A, Cheerie, D, Guirguis, G, Hou, H, Yuki, KE, Haque, B, Thiruvahindrapuram, B, Marshall, CR, Mendoza-Londono, R, Shlien, A, Kyriakopoulou, LG, Walker, S, Dowling, JJ, Wilson, MD, and Costain, G
Abstract: Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq). There was no evidence of a frameshift, nor of reduced expression consistent with nonsense-mediated decay, for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame insertions or deletions, 3.6% resulted in full exon skipping (in frame), and 0.6% resulted in full intron inclusion (in frame). Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. The predicted impact on splicing using (1) SpliceAI, (2) MaxEntScan, and (3) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63%, and 61% of CSSVs, respectively. In summary, approximately one in four rare CSSVs did not show evidence for LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.
Published: 2024

3. P249: Gaps in the phenotype descriptions of ultra-rare genetic conditions: Review and multi-center consensus reporting guidelines

Author: AlMail, A, Jamjoom, A, Pan, A, Feng, A, Chau, V, D'Gama, A, Howell, K, Yan Liang, NS, McTague, A, Poduri, A, Wiltrout, K, Bassett, A, Christodoulou, J, Dupuis, L, Gill, P, Levy, T, Siper, P, Stark, Z, Vorstman, J, Diskin, C, Jewitt, N, Baribeau, D, Costain, G, AlMail, A, Jamjoom, A, Pan, A, Feng, A, Chau, V, D'Gama, A, Howell, K, Yan Liang, NS, McTague, A, Poduri, A, Wiltrout, K, Bassett, A, Christodoulou, J, Dupuis, L, Gill, P, Levy, T, Siper, P, Stark, Z, Vorstman, J, Diskin, C, Jewitt, N, Baribeau, D, and Costain, G
Published: 2024

4. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Author: D'Gama, AM, Mulhern, S, Sheidley, BR, Boodhoo, F, Buts, S, Chandler, NJ, Cobb, J, Curtis, M, Higginbotham, E, Holland, J, Khan, T, Koh, J, Yliang, NS, Mcrae, L, Nesbitt, SE, Oby, BT, Paternoster, B, Patton, A, Rose, G, Scotchman, E, Valentine, R, Wiltrout, KN, Hayeems, RZ, Jain, P, Lunke, S, Marshall, CR, Rockowitz, S, Sebire, N, Stark, Z, White, SM, Chitty, LS, Cross, JH, Scheffer, IE, Chau, V, Costain, G, Poduri, A, Howell, KB, McTague, A, D'Gama, AM, Mulhern, S, Sheidley, BR, Boodhoo, F, Buts, S, Chandler, NJ, Cobb, J, Curtis, M, Higginbotham, E, Holland, J, Khan, T, Koh, J, Yliang, NS, Mcrae, L, Nesbitt, SE, Oby, BT, Paternoster, B, Patton, A, Rose, G, Scotchman, E, Valentine, R, Wiltrout, KN, Hayeems, RZ, Jain, P, Lunke, S, Marshall, CR, Rockowitz, S, Sebire, N, Stark, Z, White, SM, Chitty, LS, Cross, JH, Scheffer, IE, Chau, V, Costain, G, Poduri, A, Howell, KB, and McTague, A
Abstract: BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis w
Published: 2023

5. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author: Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.
Abstract: 01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
Published: 2023

6. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Author: Gehin, C., Lone, M.A., Lee, W., Capolupo, L., Ho, S., Adeyemi, A.M., Gerkes, E.H., Stegmann, A.P.A., López-Martín, E., Bermejo-Sánchez, E., Martínez-Delgado, B., Zweier, C., Kraus, C., Popp, B., Strehlow, V., Gräfe, D., Knerr, I., Jones, E.R., Zamuner, S., Abriata, L.A., Kunnathully, V., Moeller, B.E., Vocat, A., Rommelaere, S., Bocquete, J.P., Ruchti, E., Limoni, G., Campenhoudt, M. Van, Bourgeat, S., Henklein, P., Gilissen, C.F., Bon, B.W.M. van, Pfundt, R.P., Willemsen, M.H., Schieving, J.H., Leonardi, E., Soli, F., Murgia, A., Guo, H, Zhang, Qiumeng, Xia, K., Fagerberg, C.R., Beier, C.P., Larsen, M.J., Valenzuela, I., Fernández-Álvarez, P., Xiong, S., Śmigiel, R., López-González, V., Armengol, L., Morleo, M., Selicorni, A., Torella, A., Blyth, M., Cooper, N.S., Wilson, V., Oegema, R., Herenger, Y., Garde, A., Bruel, A.L., Tran Mau-Them, F., Maddocks, A.B., Bain, J.M., Bhat, M.A., Costain, G., Kannu, P., Marwaha, A., Champaigne, N.L., Friez, M.J., Richardson, E.B., Gowda, V.K., Srinivasan, V.M., Gupta, Y., Lim, T.Y., Sanna-Cherchi, S., Lemaitre, B., Yamaji, T., Hanada, K., Burke, J.E., Jakšić, A.M., McCabe, B.D., Los Rios, P. De, Hornemann, T., D'Angelo, G., Gennarino, V.A., Gehin, C., Lone, M.A., Lee, W., Capolupo, L., Ho, S., Adeyemi, A.M., Gerkes, E.H., Stegmann, A.P.A., López-Martín, E., Bermejo-Sánchez, E., Martínez-Delgado, B., Zweier, C., Kraus, C., Popp, B., Strehlow, V., Gräfe, D., Knerr, I., Jones, E.R., Zamuner, S., Abriata, L.A., Kunnathully, V., Moeller, B.E., Vocat, A., Rommelaere, S., Bocquete, J.P., Ruchti, E., Limoni, G., Campenhoudt, M. Van, Bourgeat, S., Henklein, P., Gilissen, C.F., Bon, B.W.M. van, Pfundt, R.P., Willemsen, M.H., Schieving, J.H., Leonardi, E., Soli, F., Murgia, A., Guo, H, Zhang, Qiumeng, Xia, K., Fagerberg, C.R., Beier, C.P., Larsen, M.J., Valenzuela, I., Fernández-Álvarez, P., Xiong, S., Śmigiel, R., López-González, V., Armengol, L., Morleo, M., Selicorni, A., Torella, A., Blyth, M., Cooper, N.S., Wilson, V., Oegema, R., Herenger, Y., Garde, A., Bruel, A.L., Tran Mau-Them, F., Maddocks, A.B., Bain, J.M., Bhat, M.A., Costain, G., Kannu, P., Marwaha, A., Champaigne, N.L., Friez, M.J., Richardson, E.B., Gowda, V.K., Srinivasan, V.M., Gupta, Y., Lim, T.Y., Sanna-Cherchi, S., Lemaitre, B., Yamaji, T., Hanada, K., Burke, J.E., Jakšić, A.M., McCabe, B.D., Los Rios, P. De, Hornemann, T., D'Angelo, G., and Gennarino, V.A.
Abstract: Item does not contain fulltext, Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
Published: 2023

7. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Author: Scala, M., Nishikawa, M., Ito, H., Tabata, H., Khan, T., Accogli, A., Davids, L., Ruiz, A., Chiurazzi, Pietro, Cericola, G., Schulte, B., Monaghan, K. G., Begtrup, A., Torella, A., Pinelli, M., Denomme-Pichon, A. -S., Vitobello, A., Racine, C., Mancardi, M. M., Kiss, C., Guerin, A., Wu, W., Vila, E. G., Mak, B. C., Martinez-Agosto, J. A., Gorin, M. B., Duz, B., Bayram, Y., Carvalho, C. M. B., Vengoechea, J. E., Chitayat, D., Tan, T. Y., Callewaert, B., Kruse, B., Bird, L. M., Faivre, L., Zollino, Marcella, Biskup, S., Striano, P., Nigro, V., Severino, M., Capra, V., Costain, G., Nagata, K. -I., Brown, G., Butte, M. J., Dell'Angelica, E. C., Dorrani, N., Douine, E. D., Fogel, B. L., Gutierrez, I., Huang, A., Krakow, D., Lee, H., Loo, S. K., Martin, M. G., Mcgee, E., Nelson, S. F., Nieves-Rodriguez, S., Palmer, C. G. S., Papp, J. C., Parker, N. H., Renteria, G., Sinsheimer, J. S., Wan, J., Wang, L. -K., Perry, K. W., Brunetti-Pierri, N., Casari, G., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Scala, Marcello, Nishikawa, Masashi, Ito, Hidenori, Tabata, Hidenori, Khan, Tayyaba, Accogli, Andrea, Davids, Laura, Ruiz, Anna, Chiurazzi, Pietro, Cericola, Gabriella, Schulte, Björn, Monaghan, Kristin G, Begtrup, Amber, Torella, Annalaura, Pinelli, Michele, Denommé-Pichon, Anne Sophie, Vitobello, Antonio, Racine, Caroline, Mancardi, Maria Margherita, Kiss, Courtney, Guerin, Andrea, Wu, Wendy, Gabau Vila, Elisabeth, Mak, Bryan C, Martinez-Agosto, Julian A, Gorin, Michael B, Duz, Bugrahan, Bayram, Yavuz, Carvalho, Claudia M B, Vengoechea, Jaime E, Chitayat, David, Tan, Tiong Yang, Callewaert, Bert, Kruse, Bernd, Bird, Lynne M, Faivre, Laurence, Zollino, Marcella, Biskup, Saskia, Striano, Pasquale, Nigro, Vincenzo, Severino, Mariasavina, Capra, Valeria, Costain, Gregory, Nagata, Koh Ichi, and Nagata, Koh-Ichi
Subjects: brain development, Settore MED/03 - GENETICA MEDICA, Medical and Health Sciences, Telethon Undiagnosed Diseases Program, Mice, Neurodevelopmental Disorder, Medicine and Health Sciences, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, Neurons, Pediatric, neuronal migration, Neurology & Neurosurgery, Animal, axon guidance, Psychology and Cognitive Sciences, p21-Activated Kinase, Neurosciences, Biology and Life Sciences, Undiagnosed Diseases Network, Neuron, rac GTP-Binding Proteins, Brain Disorders, RAC3, Phenotype, p21-Activated Kinases, Neurodevelopmental Disorders, small GTPase, Neurological, Congenital Structural Anomalies, Neurology (clinical), Human
Abstract: Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.
Published: 2022

8. Caregiver and Adult Patient Perspectives on the Importance of a Diagnosis of 22q11.2 Deletion Syndrome

Author: Costain, G., Chow, E. W. C., and Ray, P. N.
Abstract: Background: Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help justify widespread use of new and expensive genetic technologies. Methods: We conducted a survey of caregivers on the value of a genetic/aetiologic diagnosis of 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in ID. We also surveyed the opinion of a high-functioning subset of adults with 22q11.2DS themselves. We used standard quantitative and qualitative methods to analyse the responses. Results: In total, 73 of 118 surveys were returned (61.9%). There was convergence of quantitative and qualitative results, and consistency between adult patient and caregiver responses. A definitive molecular diagnosis of 22q11.2DS was a critical event with diverse positive repercussions, even if occurring later in life. Frequently cited benefits included greater understanding and certainty, newfound sense of purpose and a platform for advocacy, and increased opportunities to optimise medical, social and educational needs. Conclusions: This is the first study to characterise the impact of a diagnosis of this representative microdeletion syndrome on adult patients and their families. The results both validate and expand on the theoretical benefits proposed by clinicians and researchers. The use of genome-wide microarray technologies will provide an increasing number of molecular diagnoses. The importance of a diagnosis of 22q11.2DS demonstrated here therefore has implications for changing attitudes about molecular genetic diagnosis that could benefit individuals with ID of currently unknown cause and their families.
Published: 2012
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9. Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

Author: Costain G and Bassett AS
Subjects: Medicine (General), R5-920, Genetics, QH426-470
Abstract: Gregory Costain1,2, Anne S Bassett1–41Clinical Genetics Research Program, Centre for Addiction and Mental Health, 2Institute of Medical Science, University of Toronto, 3Division of Cardiology, Department of Medicine and Department of Psychiatry, University Health Network, 4Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaAbstract: Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expression) of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletion syndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also propose new directions for research involving general genetic risk prediction and counseling in schizophrenia.Keywords: schizophrenia, genetics, 22q11 deletion syndrome, copy number variation, genetic counseling, genetic predisposition to disease
Published: 2012

10. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author: Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, Tan, TY, Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, and Tan, TY
Abstract: Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
Published: 2022

11. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Author: Scala, M, Nishikawa, M, Ito, H, Tabata, H, Khan, T, Accogli, A, Davids, L, Ruiz, A, Chiurazzi, P, Cericola, G, Schulte, B, Monaghan, KG, Begtrup, A, Torella, A, Pinelli, M, Denomme-Pichon, AS, Vitobello, A, Racine, C, Mancardi, MM, Kiss, C, Guerin, A, Wu, W, Vila, EG, Mak, BC, Martinez-Agosto, JA, Gorin, MB, Duz, B, Bayram, Y, Carvalho, CMB, Vengoechea, JE, Chitayat, D, Tan, TY, Callewaert, B, Kruse, B, Bird, LM, Faivre, L, Zollino, M, Biskup, S, Striano, P, Nigro, V, Severino, M, Capra, V, Costain, G, Nagata, K-I, Scala, M, Nishikawa, M, Ito, H, Tabata, H, Khan, T, Accogli, A, Davids, L, Ruiz, A, Chiurazzi, P, Cericola, G, Schulte, B, Monaghan, KG, Begtrup, A, Torella, A, Pinelli, M, Denomme-Pichon, AS, Vitobello, A, Racine, C, Mancardi, MM, Kiss, C, Guerin, A, Wu, W, Vila, EG, Mak, BC, Martinez-Agosto, JA, Gorin, MB, Duz, B, Bayram, Y, Carvalho, CMB, Vengoechea, JE, Chitayat, D, Tan, TY, Callewaert, B, Kruse, B, Bird, LM, Faivre, L, Zollino, M, Biskup, S, Striano, P, Nigro, V, Severino, M, Capra, V, Costain, G, and Nagata, K-I
Abstract: Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical ne
Published: 2022

12. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Author: Davies, R. W., Fiksinski, A. M., Breetvelt, E. J., Williams, N. M., Hooper, S. R., Monfeuga, T., Bassett, A. S., Owen, M. J., Gur, R. E., Morrow, B. E., McDonald-McGinn, D. M., Swillen, A., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., van Amelsvoort, T., Arango, C., Armando, M., Campbell, L. E., Cubells, J. F., Eliez, S., Garcia-Minaur, S., Gothelf, D., Kates, W. R., Murphy, K. C., Murphy, C. M., Murphy, D. G., Philip, N., Repetto, G. M., Shashi, V., Simon, T. J., Suner, D. H., Vicari, Stefano, Scherer, S. W., Epstein, M. P., Warren, S. T., Morrison, S., Chawner, S., Vingerhoets, C., Breckpot, J., Vergaelen, E., Vogels, A., Monks, S., Prasad, S. E., Sandini, C., Schneider, M., Maeder, J., Fraguas, D., Evers, R., Tassone, F., Morey-Canyelles, J., Ousley, O. Y., Antshel, K. M., Fremont, W., Fritsch, R., Ornstein, C., Daly, E. M., Costain, G. A., Boot, E., Heung, T., Crowley, T. B., Zackai, E. H., Calkins, M. E., Gur, R. C., Mccabe, K. L., Busa, T., Schoch, K., Pontillo, M., Duijff, S. N., Kahn, R. S., Houben, Mariasofia, Kushan, L., Jalbrzikowski, M., Carmel, M., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Bearden, C. E., Vorstman, J. A. S., Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: MA Med Staf Spec Psychiatrie (9)
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, [SDV]Life Sciences [q-bio], INTELLIGENCE, Medical and Health Sciences, Cohort Studies, ddc:616.89, 0302 clinical medicine, Borderline intellectual functioning, Risk Factors, Intellectual disability, 2.1 Biological and endogenous factors, PREMORBID IQ, Cognitive decline, Aetiology, Child, ComputingMilieux_MISCELLANEOUS, Intelligence quotient, ABNORMALITIES, General Medicine, Middle Aged, Serious Mental Illness, Mental Health, Phenotype, Schizophrenia, 030220 oncology & carcinogenesis, Child, Preschool, Cohort, Female, Clinical psychology, Adult, Psychosis, Adolescent, Immunology, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, PSYCHOSIS, Clinical Research, Intellectual Disability, Genetic variation, Behavioral and Social Science, mental disorders, medicine, Genetics, DiGeorge Syndrome, Humans, Cognitive Dysfunction, Preschool, METAANALYSIS, International 22q11.2 Brain and Behavior Consortium, Aged, DECLINE, reliability, business.industry, Prevention, cognitive-development, Genetic Variation, PERFORMANCE, medicine.disease, Brain Disorders, schizophrenia, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business
Abstract: The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.Polygenic risk scores are nearing a level of differentiation required for their clinical utility in risk prediction in populations with high-risk rare pathogenic genetic variants.
Published: 2020
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13. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria

Author: Vetro, A, Nielsen, HN, Holm, R, Hevner, RF, Parrini, E, Powis, Z, Moller, RS, Bellan, C, Simonati, A, Lesca, G, Helbig, KL, Palmer, EE, Mei, D, Ballardini, E, Van Haeringen, A, Syrbe, S, Leuzzi, V, Cioni, G, Curry, CJ, Costain, G, Santucci, M, Chong, K, Mancini, GMS, Clayton-Smith, J, Bigoni, S, Scheffer, IE, Dobyns, WB, Vilsen, B, Guerrini, R, Vetro, A, Nielsen, HN, Holm, R, Hevner, RF, Parrini, E, Powis, Z, Moller, RS, Bellan, C, Simonati, A, Lesca, G, Helbig, KL, Palmer, EE, Mei, D, Ballardini, E, Van Haeringen, A, Syrbe, S, Leuzzi, V, Cioni, G, Curry, CJ, Costain, G, Santucci, M, Chong, K, Mancini, GMS, Clayton-Smith, J, Bigoni, S, Scheffer, IE, Dobyns, WB, Vilsen, B, and Guerrini, R
Abstract: Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and al
Published: 2021

14. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

Author: Karas, D. J., Costain, G., Chow, E. W. C., and Bassett, A. S.
Published: 2014
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15. Hereditary Mucin Deficiency Caused by Biallelic Loss-of-Function of MUC5B Defines a Novel Category of Lung Disease

Author: Liu, Z., primary, Costain, G., additional, Goczi, A., additional, Albulescu, A., additional, Walker, S., additional, Ngan, B., additional, Hall, D.A., additional, Marshall, C.R., additional, Mennella, V., additional, Kesimer, M., additional, Knowles, M., additional, Zariwala, M.A., additional, and Dell, S.D., additional
Published: 2020
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16. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author: Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), Bhoj, E.J. (Elizabeth J.), Bryant, L. (Laura), Li, D. (Dong), Cox, S.G. (Samuel G.), Marchione, D. (Dylan), Joiner, E.F. (Evan F.), Wilson, K. (Khadija), Janssen, K. (Kevin), Lee, P. (Pearl), March, K. (Keith), Nair, D. (Divya), Sherr, E. (Elliott), Fregeau, B. (Brieana), Wierenga, K.J. (Klaas J.), Wadley, A. (Alexandrea), Mancini, G.M.S. (Grazia), Powell-Hamilton, N. (Nina), Kamp, J.J.P. (Jacques) van de, Grebe, T. (Theresa), Dean, J. (John), Ross, A.J. (Alison), Crawford, H.P. (Heather P.), Powis, Z. (Zoe), Cho, M.T. (Megan T.), Willing, M.C. (Marcia C.), Manwaring, L. (Linda), Schot, R. (Rachel), Nava, C. (Caroline), Afenjar, A. (Alexandra), Lessel, D. (Davor), Wagner, M. (Matias), Klopstock, T. (Thomas), Winkelmann, B., Catarino, C.B. (Claudia B.), Retterer, K. (Kyle), Schuette, J.L. (Jane L.), Innis, J.W. (Jeffrey), Pizzino, A. (Amy), Lüttgen, S. (Sabine), Denecke, J. (Jonas), Strom, T.M. (Tim), Monaghan, K.G. (Kristin G.), Yuan, Z.-F. (Zuo-Fei), Dubbs, H. (Holly), Bend, R. (Renee), Lee, J.A. (Jennifer A.), Lyons, M.J. (Michael J.), Hoefele, J. (Julia), Günthner, R. (Roman), Reutter, H. (Heiko), Keren, B. (Boris), Radtke, K. (Kelly), Sherbini, O. (Omar), Mrokse, C. (Cameron), Helbig, K.L. (Katherine L.), Odent, S. (Sylvie), Cogne, B. (Benjamin), Mercier, S. (Sandra), Bezieau, S. (Stephane), Besnard, T. (Thomas), Kury, S. (Sebastien), Redon, R. (Richard), Reinson, K. (Karit), Wojcik, M.H. (Monica H.), Õunap, K. (Katrin), Ilves, P. (Pilvi), Innes, A.M. (A Micheil), Kernohan, K.D. (Kristin), Costain, G. (Gregory), Meyn, M.S. (M Stephen), Chitayat, D. (David), Zackai, E. (Elaine), Lehman, A. (Anna), Kitson, H. (Hilary), Martin, M.G. (Martin G.), Martinez-Agosto, J.A. (Julian A.), Nelson, S.F. (Stan F.), Palmer, C.G.S. (Christina G S), Papp, J.C. (Jeanette C.), Parker, N.H. (Neil H.), Sinsheimer, J.S. (Janet S.), Vilain, E. (Eric), Wan, J. (Jijun), Yoon, A.J. (Amanda J.), Zheng, A. (Allison), Brimble, E. (Elise), Ferrero, G.B. (Giovanni Battista), Radio, F.C. (Francesca Clementina), Carli, D. (Diana), Barresi, S. (Sabina), Brusco, A. (Alfredo), Tartaglia, M. (Marco), Thomas, J.M. (Jennifer Muncy), Umana, L. (Luis), Weiss, M.M. (Marjan M.), Gotway, G. (Garrett), Stuurman, K.E. (Kyra), Thompson, M.L. (Michelle L.), McWalter, K. (Kirsty), Stumpel, C.T.R.M. (Constance T R M), Stevens, S.J.C. (Servi J C), Stegmann, A.P.A. (Alexander P A), Tveten, K. (Kristian), Vøllo, A. (Arve), Prescott, T. (Trine), Fagerberg, C. (Christina), Laulund, L.W. (Lone Walentin), Larsen, M.J. (Martin J.), Byler, M. (Melissa), Lebel, R.R. (Robert Roger), Hurst, A.C. (Anna C.), Dean, J. (Joy), Schrier Vergano, S.A. (Samantha A.), Norman, J. (Jennifer), Mercimek-Andrews, S. (Saadet), Neira, J. (Juanita), Van Allen, M.I. (Margot I.), Longo, N. (Nicola), Sellars, E. (Elizabeth), Louie, R.J. (Raymond J.), Cathey, S.S. (Sara S.), Brokamp, E. (Elly), Héron, D. (Delphine), Snyder, M. (Molly), Vanderver, A. (Adeline), Simon, C. (Celeste), de la Cruz, X. (Xavier), Padilla, N. (Natália), Crump, J.G. (J Gage), Chung, W. (Wendy), Garcia, B. (Benjamin), Hakonarson, H. (Hakon), and Bhoj, E.J. (Elizabeth J.)
Abstract: Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
Published: 2020
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17. Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

Author: Kumar, R, Palmer, E, Gardner, AE, Carroll, R, Banka, S, Abdelhadi, O, Donnai, D, Elgersma, Y, Curry, CJ, Gardham, A, Suri, M, Malla, R, Brady, LI, Tarnopolsky, M, Azmanov, DN, Atkinson, V, Black, M, Baynam, G, Dreyer, L, Hayeems, RZ, Marshall, CR, Costain, G, Wessels, MW, Baptista, J, Drummond, J, Leffler, M, Field, M, Gecz, J, Kumar, R, Palmer, E, Gardner, AE, Carroll, R, Banka, S, Abdelhadi, O, Donnai, D, Elgersma, Y, Curry, CJ, Gardham, A, Suri, M, Malla, R, Brady, LI, Tarnopolsky, M, Azmanov, DN, Atkinson, V, Black, M, Baynam, G, Dreyer, L, Hayeems, RZ, Marshall, CR, Costain, G, Wessels, MW, Baptista, J, Drummond, J, Leffler, M, Field, M, and Gecz, J
Abstract: Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals’ has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.
Published: 2020

18. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Author: Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., Chopra, P., Cutler, D. J., Duncan, R., Kotlar, A. V., Mulle, J. G., Voss, A. J., Zwick, M. E., Diacou, A., Golden, A., Guo, T., Lin, J. -R., Wang, T., Zhang, Z., Zhao, Yu Yang, Marshall, C., Merico, D., Jin, A., Lilley, B., Salmons, H. I., Tran, O., Holmans, P., Pardinas, A., Walters, J. T. R., Demaerel, W., Boot, E., Butcher, N. J., Costain, G. A., Lowther, C., Evers, R., van Amelsvoort, T. A. M. J., van Duin, E., Vingerhoets, C., Breckpot, J., Devriendt, K., Vergaelen, E., Vogels, A., Crowley, T. B., Mcginn, D. E., Moss, E. M., Sharkus, R. J., Unolt, M., Zackai, E. H., Calkins, M. E., Gallagher, R. S., Gur, R. C., Tang, S. X., Fritsch, R., Ornstein, C., Repetto, G. M., Breetvelt, E., Duijff, S. N., Fiksinski, A., Moss, H., Niarchou, M., Murphy, K. C., Prasad, S. E., Daly, E. M., Gudbrandsen, M., Murphy, C. M., Murphy, D. G., Buzzanca, A., Fabio, F. D., Digilio, M. C., Pontillo, M., Marino, B., Vicari, Stefano, Coleman, K., Cubells, J. F., Ousley, O. Y., Carmel, M., Gothelf, D., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Weizman, A., Kushan, L., Jalbrzikowski, M., Armando, M., Eliez, S., Sandini, C., Schneider, M., Bena, F. S., Antshel, K. M., Fremont, W., Kates, W. R., Belzeaux, R., Busa, T., Philip, N., Campbell, L. E., Mccabe, K. L., Hooper, S. R., Schoch, K., Shashi, V., Simon, T. J., Tassone, F., Arango, C., Fraguas, D., Garcia-Minaur, S., Morey-Canyelles, J., Rosell, J., Suner, D. H., Raventos-Simic, J., Epstein, M. P., Williams, N. M., Bassett, A. S., Zhao Y., Vicari S. (ORCID:0000-0002-5395-2262), Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., Chopra, P., Cutler, D. J., Duncan, R., Kotlar, A. V., Mulle, J. G., Voss, A. J., Zwick, M. E., Diacou, A., Golden, A., Guo, T., Lin, J. -R., Wang, T., Zhang, Z., Zhao, Yu Yang, Marshall, C., Merico, D., Jin, A., Lilley, B., Salmons, H. I., Tran, O., Holmans, P., Pardinas, A., Walters, J. T. R., Demaerel, W., Boot, E., Butcher, N. J., Costain, G. A., Lowther, C., Evers, R., van Amelsvoort, T. A. M. J., van Duin, E., Vingerhoets, C., Breckpot, J., Devriendt, K., Vergaelen, E., Vogels, A., Crowley, T. B., Mcginn, D. E., Moss, E. M., Sharkus, R. J., Unolt, M., Zackai, E. H., Calkins, M. E., Gallagher, R. S., Gur, R. C., Tang, S. X., Fritsch, R., Ornstein, C., Repetto, G. M., Breetvelt, E., Duijff, S. N., Fiksinski, A., Moss, H., Niarchou, M., Murphy, K. C., Prasad, S. E., Daly, E. M., Gudbrandsen, M., Murphy, C. M., Murphy, D. G., Buzzanca, A., Fabio, F. D., Digilio, M. C., Pontillo, M., Marino, B., Vicari, Stefano, Coleman, K., Cubells, J. F., Ousley, O. Y., Carmel, M., Gothelf, D., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Weizman, A., Kushan, L., Jalbrzikowski, M., Armando, M., Eliez, S., Sandini, C., Schneider, M., Bena, F. S., Antshel, K. M., Fremont, W., Kates, W. R., Belzeaux, R., Busa, T., Philip, N., Campbell, L. E., Mccabe, K. L., Hooper, S. R., Schoch, K., Shashi, V., Simon, T. J., Tassone, F., Arango, C., Fraguas, D., Garcia-Minaur, S., Morey-Canyelles, J., Rosell, J., Suner, D. H., Raventos-Simic, J., Epstein, M. P., Williams, N. M., Bassett, A. S., Zhao Y., and Vicari S. (ORCID:0000-0002-5395-2262)
Abstract: Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.
Published: 2020

19. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes the TRIGR randomized clinical trial

Author: Knip M., Akerblom H. K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H. -M., Dupre J., Fraser W. D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J. P., Lawson M. L., Ludvigsson J., Madacsy L., Mahon J. L., Ormisson A., Palmer J. P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N. H., Virtanen S. M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S. P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D. W., Brown C., Craig M., Johnston A., Bere L. J., Clarson C. L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J. -P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D. K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H. J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E. A. C., Woo V., Boland A., Clark H. D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J. C., Sauro V., Tawagi G. F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M. J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M. -C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E. A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J. C., Dawson C., Joyce C., Newhook L. A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M. J., Penner M., Sankaran K., Hardy-Brown K., King N., White R. A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M. -A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H. -M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A. -L., Hamalainen A. -M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A. S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S. -L., Selvenius J., Siljander H., Haanpaa P. -L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A. -M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A. R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M. -L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M. -L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G. B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y. M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M. B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J. A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J. R., Chueca M., Cortazar A., Echarte G., Frutos T. G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M. T., Hawkins F. G., Hernandez R., Herranz L., Pallardo L. F., Deibarra L. S., Fernandez B. H., Luis J. L., Ortiz-Quintana L., Recarte P. P., Arnau D. R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A. -M., Konefal M. S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A. -K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A. -B., Lyden G. -B., Nilsson N. -O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T. O., Andersson A. -C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I. -B., Strigard E., Svensson B. -L., Aman J., Breivik G. -E., Detlofsson I. -L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M. E., Gilmour C., Klein M. B., Lain C., Salerno D., Smith M. E., Vats K., Pfaff D. J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., Pediatrics, Knip M., Akerblom H.K., Altaji E., Becker D., Bruining J., Castano L., Danne T., De Beaufort C., Dosch H.-M., Dupre J., Fraser W.D., Howard N., Ilonen J., Konrad D., Kordonouri O., Krischer J.P., Lawson M.L., Ludvigsson J., Madacsy L., Mahon J.L., Ormisson A., Palmer J.P., Pozzilli P., Savilahti E., Serrano-Rios M., Songini M., Taback S., Vaarala O., White N.H., Virtanen S.M., Wasikowa R., Mandrup-Poulsen T., Arjas E., Lernmark A., Laara E., Schmidt B., Hyytinen M., Koski K., Koski M., Merentie K., Pajakkala E., Reunanen A., Salonen M., Terhonen T., Virkkunen S., Cuthbertson D., Gainer B., Hadley D., Malloy J., Nallamshetty L., Shanker L., Bradley B., Lough G., Fraser W., Sermer M., Taback S.P., Franciscus M., Nucci A., Palmer J., Alahuhta K., Barlund S., Korhonen T., Kovanen L., Lehtonen E., Niinisto S., Pekkala M., Sorkio S., Toivanen L., Vahatalo L., Uusitalo U., Ohman T., Bongiorno R., Catteau J., Fraser G., Lloyd M., Crock P., Giles M., Siech K., See D.W., Brown C., Craig M., Johnston A., Bere L.J., Clarson C.L., Jenner M., McManus R., Renato N., Lovell M., Higo D., Kent N., Kwan J., Marshall C., Metzger D., Chanoine J.-P., Stewart L., Thompson D., Edwards A., Lange I., Mercer J., Pacaud D., Josephine H., Schwarz W., Stephure D.K., Boer J., Chatur T., Chick C., Couch B., Demianczuk N., Girgis R., Marks S., Ryan E., Thompson M., Dean H.J., Grant L., Hamelin K., LaForte J., Murphy L., Catte D., Schneider C., Sellers E.A.C., Woo V., Boland A., Clark H.D., Cooper T., Gruslin A., Karovitch A., Keely E., Malcolm J.C., Sauro V., Tawagi G.F., Andrighetti S., Arnold G., Barrett J., Blumer I., Daneman D., Donat D., Ehrlich R., Feig D., Gottesman I., Gysler M., Karkanis S., Kenshole A., Knight B., Lackie E., Lewis V., Martin M.J., Maxwell C., Oliver G., Panchum P., Shilletto N., Simone A., Skidmore M., Turrini T., Wong S., Allen C., Belanger L., Bouchard I., Ferland S., Frenette L., Garrido-Russo M., Leblanc M., Imbeault J., Morin V., Olivier G., Weisnagell J., Costain G., Dornan J., Heath K., MacSween M.-C., McGibbon A., Ramsay C., Sanderson F., Sanderson S., Benabdesselam L., Gonthier M., Huot C., Thibeault M., Laforte D., Legault L., Perron P., Armson A., Canning P., Cummings E.A., Ivanko V., McLeod L., Mokashi A., Scott K., Bridger T., Crane J., Crummell C., Curtis J.C., Dawson C., Joyce C., Newhook L.A., Newman S., Druken E., Begum-Hasan J., Breen A., Houlden R., Woods M., Carrson G., Kelly S., Martel M.J., Penner M., Sankaran K., Hardy-Brown K., King N., White R.A., Park M., Popkin J., Robson L., Coles K., Al Taji E., Cerna M., Cerny M., Francova H., Hainerova I., Kothankova H., Koukalova R., Krakorova V., Mendlova P., Sitova R., Stechova K., Vavrinec J., Vosahlo J., Zlatohlavkova B., Brazdova L., Faksova P., Gregorova D., Kantor L., Malkova K., Venhacova J., Venhacova P., Cipra A., Skvor J., Budejovice C., Tomsikova Z., Botkova-Krauseova H., Mockova A., Paterova P., Gogelova P., Kandrnalova J., Einberg U., Jakovlev U., Posiadlo S., Rannaste E., Raukas R., Riikjarv M.-A., Valla K., Astover V., Kirss A., Retpap J., Taht E., Tillmann V., Vahtra S., Heikkila M., Hirvasniemi M., Luopajarvi K., Johansson S., Kleemola P., Laukkanen E., Parkkola A., Pigg H.-M., Puttonen H., Renlund M., Salonen K., Suomalainen H., Tenkula T., Teramo K., Jarvenpaa A.-L., Hamalainen A.-M., Jussila R., Kiiveri S., Haavisto H., Holopainen S., Kupiainen H., Leeve T., Lumme K., Nironen T., Tenhola S., Tiilikainen T., Keinonen H., Lautala P., Salonen P., Vesanto M., Aspholm A.S., Asunta P., Ikavalko H., Jason E., Jaminki S., Kekki P., Koskinen M., Lehtimaki S., Lahde J., Makela M., Peltoniemi S., Poutiainen L., Ranta K., Salonsaari T., Sarviharju-Tujula S.-L., Selvenius J., Siljander H., Haanpaa P.-L., Holm C., Juutilainen A., Jarvelainen V., Kangaskolkka-Keskilohko A.-M., Laino E., Marjamaki L., Suominen E., Ylitalo S., Hokkanen M., Lounamaa R., Matikainen M., Nuuja A., Paalanen I., Puupponen A.R., Salo-Edwards H., Alanne S., Kultti T., Linjama H., Muhonen K., Vaaraniemi M., Talvitie T., Backman M., Hanhijarvi R., Koivula P., Lindstrom K., Martikainen A., Nurmi P., Bjork A., Huopio H., Komulainen J., Lehtomaki S., Muikku E., Pesola J., Sankilampi U., Arkkola T., Hekkala A., Jurvakainen S., Koivikko M.-L., Kahonen M., Leinonen E., Mykkanen T., Pohjola H., Riikonen K., Niittyvuopio A., Stenius A., Tapanainen P., Veijola R., Alar A., Jovio S., Korpela P., Makinen E., Hietanen L., Kivisto J., Kaar M.-L., Lehtimaki P., Mustila T., Popov E., Saatela S., Taittonen L., Ahtiainen K., Laaksonen N., Luoto M., Viitala J., Virransalo R., Nykanen P., Paajanen S., Parkkinen S., Pyrhonen H., Sarkka T., Aschemeier B., Bektas S., Biester T., Datz N., Deiss D., Fath M., Lupke K., Muller B., Nestoris C., Rothes S., Sadeghian E., Semler K., Arato A., Krikovszky D., Nobilis A., Szenasi J., Benevento D., Anguissola G.B., Biagioni M., Bizzarri C., Cherubini V., Ferrito L., Giordano C., Giorgetti C., Khazrai Y.M., Kyanvash S., Maddaloni E., Napoli A., Piergiovanni F., Pitocco D., Suraci T., Tabacco G., Valente L., Visalli N., Carboni M.B., Cavallo R., Cau V., Isola C., Ledda A., Loddo M., Mannu C., Pettinau M., Pisano S., Porceddu M., Putzu C., Rita A., Peters D., Schierloh U., Bisschoff M., Blonk L., Lappenschaar T., Manai B., Seesink M., Sperling-Conrad M., Verhagen M., Zoethout J.A., Basiak A., Chalas M., Chesiak M., Gramza A., Iwankiewicz J., Sieradzan E., Wikiera B., Ciechanowska M., Dziatkowiak H., Futona B., Gorska A., Glowacka-Wony M., Kaim I., Klich B., Starzyk J., Wolanin M., Tokarska L., Chucherco D., Deja G., Firek-Pedras M., Jarosz-Chobot P., Kalina M., Kutrowska-Adamusiak K., Minkina-Pedras M., Muchaka-Bianga M., Bodalski J., Mlynarski W., Szadkowska A., Cieslak A., Cypryk K., Dziatosz K., Jastzebowska J., Krysiak A., Szymanska U., Wilcznski J., Zawodniak-Szalapska M., Aguay A., Bilbao J.R., Chueca M., Cortazar A., Echarte G., Frutos T.G., Jimenez P., Martul P., Moreno A., Oyarzabal M., Rica I., Salgado Y., Martinez-Larrad M.T., Hawkins F.G., Hernandez R., Herranz L., Pallardo L.F., Deibarra L.S., Fernandez B.H., Luis J.L., Ortiz-Quintana L., Recarte P.P., Arnau D.R., Aronsson L., Boden S., Fredriksson J., Isacsson E., Johansson I., Karlsson E., Lock C., Sandstrom A.-M., Konefal M.S., Andreasson C., Dahlstrom U., Hanas R., Lundqvist K., Windell L., Jansson I., Karlsson A.-K., Lindbladh B., Odenman I., Pettersson C., Sundberg F., Sundqvist M., Aronsson S., Bellman I., Bengtsson A.-B., Lyden G.-B., Nilsson N.-O., Soderblom M., Unt C., Augustsson M., Bengtsson M., Fors H., Helmrich A., Johansson T.O., Andersson A.-C., Boiard-Stomlid A., Hellgren G., Kallsholm H., Lindqvist J., Nilsson M., Nordwall M., Stromstedt C., Ahsberg C., Lindh A., Lindhe C., Samuelsson C., Wiik A., Edenwall H., Ljumgcrantz M., Persson I.-B., Strigard E., Svensson B.-L., Aman J., Breivik G.-E., Detlofsson I.-L., Kroon M., Sarnblad S., Johansson C., Ilvered R., Lundberg A., Akesson K., Beccarelli A., Gadient M., Rappold-Amrein C., Schoenle E., Daftary A., Damagro-Elias M.E., Gilmour C., Klein M.B., Lain C., Salerno D., Smith M.E., Vats K., Pfaff D.J., Malone P., Mansfield P., Munns M., Nickel K., Pompilio K., Siemion W., Taculad R., Van Horn K., Zdanadewic M., Chambliss C., Jones J., Sadler M., Tanner-Blasiar M., Bell C., Camper N., Devaskar S., Devaskar U., Horowitz H., Rogers L., Shannahan R., Silk K., Bermudez Z., Colon R., Frazer T., Martinez-Nieves B., Torres J., Vega J., Chan M., Cook S., Goland R., Greenberg E., Jules N., Montes J., Nelson M., Parra-Valencia Z., Schachner H., Softness B., Kiviniemi M., Suomenin R., Alexander A., Hyrckowian E., Nichol L., Trucco M., Karjalainen E., Louhio T., Sarnesto A., Valtonen E., Davydova B., Helander S., Hamalainen J., Harkonen T., Joutsjoki L., Kararic M., Latva-Koivisto M., Lonn E., Nurmi T., Ollila I., Rinkinen J., Ronkainen M., Tukiainen H., Cederlof A., Kiikeri M., Tsupari S., Cheng R., Bryant K., Chan Y., Maezawa Y., Paltser G., Rasavi R., Tsui H., Winer S., Wu P., Yantha J., University of Zurich, and Knip, Mikael
Subjects: Male, Risk, medicine.medical_specialty, Casein, Breastfeeding, 030209 endocrinology & metabolism, 610 Medicine & health, 2700 General Medicine, Endocrinology and Diabetes, Disease-Free Survival, law.invention, Follow-Up Studie, Nutrition Policy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, SDG 3 - Good Health and Well-being, law, Internal medicine, Diabetes mellitus, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Child, Infant Nutritional Physiological Phenomena, Original Investigation, 2. Zero hunger, Type 1 diabetes, business.industry, Hazard ratio, Absolute risk reduction, Infant, Newborn, Caseins, General Medicine, ta3121, medicine.disease, Infant Formula, 3. Good health, Diabetes Mellitus, Type 1, Infant formula, 10036 Medical Clinic, Endokrinologi och diabetes, Female, business, Human, Follow-Up Studies
Abstract: IMPORTANCE Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. OBJECTIVE To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. DESIGN, SETTING, AND PARTICIPANTS An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. INTERVENTIONS The participants received either a casein hydrolysate or a conventional adapted cows milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. MAIN OUTCOMES AND MEASURES Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). RESULTS Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8%[95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). CONCLUSIONS AND RELEVANCE Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Funding Agencies|Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [HD040364, HD042444, HD051997]; Canadian Institutes of Health Research; Commission of the European Communities [QLK1-2002-00372]; European Foundation for the Study of Diabates/JDRF/Novo Nordisk; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research) [250114]; Dutch Diabetes Research Foundation; Finnish Diabetes Research Foundation; JDRF
Published: 2018

20. Reappraisal of reported genes for sudden arrhythmic death: an evidence-based evaluation of gene validity for Brugada syndrome

Author: Hosseini, SM, Kim, R, Udupa, S, Costain, G, Jobling, R, Liston, E, Jamal, SM, Szybowska, M, Morel, CF, Bowdin, S, Garcia, J, Care, M, Sturm, AC, Novelli, V, Ackerman, MJ, Ware, JS, Hershberger, RE, Wilde, AAM, Gollob, MH, NIH-Clinical Genome Resource Consortium, and Wellcome Trust
Subjects: CARDIAC SODIUM-CHANNEL, Science & Technology, Cardiac & Cardiovascular Systems, sudden death, National Institutes of Health Clinical Genome Resource Consortium, 1103 Clinical Sciences, VARIANTS, PHENOTYPE, LONG-QT, DISEASE, PREVALENCE, 1117 Public Health and Health Services, Peripheral Vascular Disease, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Brugada syndrome, genetics, CLINICAL GENOME RESOURCE, S422L, Life Sciences & Biomedicine, MUTATION, 1102 Cardiorespiratory Medicine and Haematology, POLYMORPHISMS
Abstract: Background -Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes. Methods -We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling three gene curation teams. Using an evidence-based semi-quantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating Limited, Moderate, Strong or Definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a Clinical Domain Expert Panel who could modify the classifications based on their independent review and consensus. Results -Of 21 genes curated for clinical validity, biocurators classified only 1 gene (SCN5A) as Definitive evidence, while all other genes were classified as Limited evidence. Following comprehensive review by the Clinical Domain Expert Panel, all 20 genes classified as Limited evidence were re-classified as Disputed in regards to any assertions of disease causality for BrS. Conclusions -Our results contest the clinical validity of all but one gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations prior to use in patient care.
Published: 2018

21. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

Author: Karas, D. J., Costain, G., Chow, E. W. C., and Bassett, A. S.
Subjects: Adult, Male, Transition to Adult Care, Middle Aged, Severity of Illness Index, Article, Caregivers, Cost of Illness, Intellectual Disability, Surveys and Questionnaires, DiGeorge Syndrome, Humans, Female, Qualitative Research
Abstract: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic subtype of intellectual disability (ID) remarkable for its constellation of congenital, developmental and later-onset features. Survival to adulthood is now the norm, and serious psychiatric illness is common in adults. However, little is known about the experiences and perceived needs of individuals with 22q11.2DS and their caregivers at time of transition from paediatric to adult models of care and beyond.We administered a mail survey to 84 caregivers of adults with 22q11.2DS and 34 adult patients themselves, inquiring about medical and social services, perceived burden and major challenges in adulthood in 22q11.2DS. Standard quantitative and qualitative methods were used to analyse the responses.Fifty-three (63.1%) caregivers and 20 (58.8%) adults with 22q11.2DS completed the survey. Perceived burden was high, with psychiatric illness and/or behavioural issues considered the most challenging aspects of adulthood in 22q11.2DS by the majority of caregivers (70.0%) and many patients themselves (42.9%). Irrespective of the extent of ID and the presence or absence of other major features, caregivers expressed dissatisfaction with medical and social services for adults, including at time of transition from paediatric care.To our knowledge, this is the first study to examine the subjective experiences of adults with 22q11.2DS and their caregivers and to identify their perceived needs for services. Better awareness of 22q11.2DS and its later-onset manifestations, early diagnosis and treatment of psychiatric illness, additional support at time of transition and dedicated clinics for adults with 22q11.2DS may help to improve patient outcomes and reduce caregiver burden.
Published: 2012

22. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome

Author: Costain, G., Chow, E. W. C., Ray, P. N., and Bassett, A. S.
Subjects: Adult, Male, Canada, Patients, Data Collection, Middle Aged, Article, Young Adult, Caregivers, Intellectual Disability, DiGeorge Syndrome, Humans, Female, Genetic Testing, Attitude to Health, Genome-Wide Association Study
Abstract: Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help justify widespread use of new and expensive genetic technologies.We conducted a survey of caregivers on the value of a genetic/aetiologic diagnosis of 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in ID. We also surveyed the opinion of a high-functioning subset of adults with 22q11.2DS themselves. We used standard quantitative and qualitative methods to analyse the responses.In total, 73 of 118 surveys were returned (61.9%). There was convergence of quantitative and qualitative results, and consistency between adult patient and caregiver responses. A definitive molecular diagnosis of 22q11.2DS was a critical event with diverse positive repercussions, even if occurring later in life. Frequently cited benefits included greater understanding and certainty, newfound sense of purpose and a platform for advocacy, and increased opportunities to optimise medical, social and educational needs.This is the first study to characterise the impact of a diagnosis of this representative microdeletion syndrome on adult patients and their families. The results both validate and expand on the theoretical benefits proposed by clinicians and researchers. The use of genome-wide microarray technologies will provide an increasing number of molecular diagnoses. The importance of a diagnosis of 22q11.2DS demonstrated here therefore has implications for changing attitudes about molecular genetic diagnosis that could benefit individuals with ID of currently unknown cause and their families.
Published: 2011

23. Individualizing Recurrence Risks for Severe Mental Illness: Epidemiologic and Molecular Genetic Approaches

Author: Costain, G., primary and Bassett, A. S., additional
Published: 2013
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24. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays

Author: Costain, G., primary, Lionel, A. C., additional, Merico, D., additional, Forsythe, P., additional, Russell, K., additional, Lowther, C., additional, Yuen, T., additional, Husted, J., additional, Stavropoulos, D. J., additional, Speevak, M., additional, Chow, E. W. C., additional, Marshall, C. R., additional, Scherer, S. W., additional, and Bassett, A. S., additional
Published: 2013
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25. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

Author: Karas, D. J., primary, Costain, G., additional, Chow, E. W. C., additional, and Bassett, A. S., additional
Published: 2012
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26. 22qII.2 Deletion Syndrome Survey

Author: Costain, G., primary, Chow, E. W. C., additional, Ray, P. N., additional, and Bassett, A. S., additional
Published: 2012
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27. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome

Author: Costain, G., primary, Chow, E. W. C., additional, Ray, P. N., additional, and Bassett, A. S., additional
Published: 2011
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28. Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions

Author: Costain, G., primary, Chow, E. W. C., additional, Silversides, C. K., additional, and Bassett, A. S., additional
Published: 2011
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29. Selecting an object-oriented process for student analysts.

Author: Costain, G.
Published: 2000
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30. A comparison of CASE-based O-O methodologies: Coad/Yourdon OOA and Booch OOD.

Author: Costain, G.
Published: 1994
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31. Organs

Author: Costain, G. A., primary
Published: 1964
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32. Selecting an object-oriented process for student analysts

Author: Costain, G., primary
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33. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author: Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael A. Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana E. Alhuzaimi, James J. Dowling, Susan Walker, Kimberly Amburgey, Robin Z. Hayeems, Lance H. Rodan, Marc A. Schwartz, Jonathan Picker, Sally A. Lynch, Aditi Gupta, Kristen J. Rasmussen, Lisa A. Schimmenti, Eric W. Klee, Zhiyv Niu, Katherine E. Agre, Ilana Chilton, Wendy K. Chung, Anya Revah-Politi, P.Y. Billie Au, Christopher Griffith, Melissa Racobaldo, Annick Raas-Rothschild, Bruria Ben Zeev, Ortal Barel, Sebastien Moutton, Fanny Morice-Picard, Virginie Carmignac, Jenny Cornaton, Nathalie Marle, Orrin Devinsky, Chandler Stimach, Stephanie Burns Wechsler, Bryan E. Hainline, Katie Sapp, Marjolaine Willems, Ange-line Bruel, Kerith-Rae Dias, Carey-Anne Evans, Tony Roscioli, Rani Sachdev, Suzanna E.L. Temple, Ying Zhu, Joshua J. Baker, Ingrid E. Scheffer, Fiona J. Gardiner, Amy L. Schneider, Alison M. Muir, Heather C. Mefford, Amy Crunk, Elizabeth M. Heise, Francisca Millan, Kristin G. Monaghan, Richard Person, Lindsay Rhodes, Sarah Richards, Ingrid M. Wentzensen, Benjamin Cogné, Bertrand Isidor, Mathilde Nizon, Marie Vincent, Thomas Besnard, Amelie Piton, Carlo Marcelis, Kohji Kato, Norihisa Koyama, Tomoo Ogi, Elaine Suk-Ying Goh, Christopher Richmond, David J. Amor, Jessica O. Boyce, Angela T. Morgan, Michael S. Hildebrand, Antony Kaspi, Melanie Bahlo, Rún Friðriksdóttir, Hildigunnur Katrínardóttir, Patrick Sulem, Kári Stefánsson, Hans Tómas Björnsson, Simone Mandelstam, Manuela Morleo, Milena Mariani, Marcello Scala, Andrea Accogli, Annalaura Torella, Valeria Capra, Mathew Wallis, Sandra Jansen, Quinten Waisfisz, Hugoline de Haan, Simon Sadedin, Sze Chern Lim, Susan M. White, David B. Ascher, Annette Schenck, Paul J. Lockhart, John Christodoulou, Tiong Yang Tan, Stephenson, S. E. M., Costain, G., Blok, L. E. R., Silk, M. A., Nguyen, T. B., Dong, X., Alhuzaimi, D. E., Dowling, J. J., Walker, S., Amburgey, K., Hayeems, R. Z., Rodan, L. H., Schwartz, M. A., Picker, J., Lynch, S. A., Gupta, A., Rasmussen, K. J., Schimmenti, L. A., Klee, E. W., Niu, Z., Agre, K. E., Chilton, I., Chung, W. K., Revah-Politi, A., Au, P. Y. B., Griffith, C., Racobaldo, M., Raas-Rothschild, A., Ben Zeev, B., Barel, O., Moutton, S., Morice-Picard, F., Carmignac, V., Cornaton, J., Marle, N., Devinsky, O., Stimach, C., Wechsler, S. B., Hainline, B. E., Sapp, K., Willems, M., Bruel, A. -L., Dias, K. -R., Evans, C. -A., Roscioli, T., Sachdev, R., Temple, S. E. L., Zhu, Y., Baker, J. J., Scheffer, I. E., Gardiner, F. J., Schneider, A. L., Muir, A. M., Mefford, H. C., Crunk, A., Heise, E. M., Millan, F., Monaghan, K. G., Person, R., Rhodes, L., Richards, S., Wentzensen, I. M., Cogne, B., Isidor, B., Nizon, M., Vincent, M., Besnard, T., Piton, A., Marcelis, C., Kato, K., Koyama, N., Ogi, T., Goh, E. S. -Y., Richmond, C., Amor, D. J., Boyce, J. O., Morgan, A. T., Hildebrand, M. S., Kaspi, A., Bahlo, M., Fridriksdottir, R., Katrinardottir, H., Sulem, P., Stefansson, K., Bjornsson, H. T., Mandelstam, S., Morleo, M., Mariani, M., Scala, M., Accogli, A., Torella, A., Capra, V., Wallis, M., Jansen, S., Weisfisz, Q., de Haan, H., Sadedin, S., Lim, S. C., White, S. M., Ascher, D. B., Schenck, A., Lockhart, P. J., Christodoulou, J., Tan, T. Y., and Human genetics
Subjects: F-box protein, Ubiquitin-Protein Ligase, Proteasome Endopeptidase Complex, F-Box-WD Repeat-Containing Protein 7, Ubiquitin-Protein Ligases, Neurodevelopment, global developmental delay, macrocephaly, Germ Cell, Article, All institutes and research themes of the Radboud University Medical Center, FBXW7, Neurodevelopmental Disorder, Genetics, Humans, hypotonia, Germ-Line Mutation, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], brain malformation, Ubiquitination, gastrointestinal issue, Germ Cells, intellectual disability, Neurodevelopmental Disorders, epilepsy, Human
Abstract: Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
Published: 2022
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34. Identification of 7alpha-, 12alpha-dihydroxy-3-oxo cholanoic acid as the major degradation product from cholic by C. perfringens.

Author: Macdonald IA, Forrest TP, Costain GA, and Rao BG
Subjects: Chenodeoxycholic Acid metabolism, Cholic Acids analysis, Hydroxysteroid Dehydrogenases metabolism, Cholic Acids metabolism, Clostridium perfringens metabolism
Published: 1978
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35. 3alpha-, 7alpha- and 12alpha-hydroxysteroid dehydrogenase activities from Clostridium perfringens.

Author: Macdonald IA, Meier EC, Mahony DE, and Costain GA
Subjects: Androsterone, Bile Acids and Salts pharmacology, Hot Temperature, Hydrogen-Ion Concentration, Kinetics, NAD pharmacology, NADP pharmacology, Clostridium perfringens enzymology, Hydroxysteroid Dehydrogenases metabolism
Abstract: 25 strains of Clostridium perfringens were screened for hydroxysteroid dehydrogenase activity; 19 contained NADP-dependent 3alpha-hydroxysteroid dehydrogenase and eight contained NAD-dependent 12alpha-hydroxysteroid dehydrogenase active against conjugated and unconjugated bile salts. All strains containing 12alpha-hydroxysteroid dehydrogenase also contained 3alpha-hydroxysteroid dehydrogenase although 12alpha-hydroxysteroid dehydrogenase was invariably in lesser quantity than the 3alpha-hydroxysteroid dehydrogenase. In addition, 7alpha-hydroxysteroid dehydrogenase activity was evident only when 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholanoate was substrate but notably absent when 3alpha, 7alpha-dihydroxy-5beta-cholanoate was substrate. The oxidation product 12alpha-hydroxy-3, 7-diketo-5beta-cholanoate is rapidly further degraded to an unknown compound devoid of either 3alpha- or 7alpha-OH groups. Group specificity of these enzymes was confirmed by thin-layer chromatography studies of the oxidation products. These enzyme systems appear to be constitutive rather than inducible. In contrast to C. perfringens. Clostridium paraputrificum (five strains tested) contained no measurable hydroxysteroid dehydrogenase activity. pH studies of the C. perfringens enzymes revealed a sharp pH optimum at pH 11.3 and 10.5 for the 3alpha-OH- and 12alpha-OH-oriented activities, respectively. Kinetic studies gave Km estimates of approx. 5 X 10(-5) and 8 X 10(-4) M with 3alpha, 7a-dihydroxy-5beta-cholanoate and 3alpha, 12alpha-dihydroxy-5beta-cholanoate as substrates for two respective enzymes. 3alpha-hydroxysteroid dehydrogenase was active against 3alpha-OH-containing steroids such as androsterone regardless of the sterochemistry of the 5H (Both A/B cis and A/B trans steroides were substrates). There was no activity against 3beta-OH-containing steroids. The 3alpha- and 12alpha-hydroxysteroid dehydrogenase activities, although differing in cofactor requirements cannot be distinguished by their appearance in the growth curve, their mobility on disc gel electrophoresis, elution volume on passage through Sephadex G-200 or heat inactivation studies.
Published: 1976
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35 results on '"Costain, G. A."'

1. P305: Evaluation of the feasibility, diagnostic yield, and utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): An international pilot study

2. A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods.

3. P249: Gaps in the phenotype descriptions of ultra-rare genetic conditions: Review and multi-center consensus reporting guidelines

4. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

5. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

6. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

7. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

8. Caregiver and Adult Patient Perspectives on the Importance of a Diagnosis of 22q11.2 Deletion Syndrome

9. Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

10. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

11. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

12. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

13. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria

14. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

15. Hereditary Mucin Deficiency Caused by Biallelic Loss-of-Function of MUC5B Defines a Novel Category of Lung Disease

16. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

17. Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

18. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

19. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes the TRIGR randomized clinical trial

20. Reappraisal of reported genes for sudden arrhythmic death: an evidence-based evaluation of gene validity for Brugada syndrome

21. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

22. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome

23. Individualizing Recurrence Risks for Severe Mental Illness: Epidemiologic and Molecular Genetic Approaches

24. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays

25. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome

26. 22qII.2 Deletion Syndrome Survey

27. Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome

28. Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions

29. Selecting an object-oriented process for student analysts.

30. A comparison of CASE-based O-O methodologies: Coad/Yourdon OOA and Booch OOD.

31. Organs

32. Selecting an object-oriented process for student analysts

33. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

34. Identification of 7alpha-, 12alpha-dihydroxy-3-oxo cholanoic acid as the major degradation product from cholic by C. perfringens.

35. 3alpha-, 7alpha- and 12alpha-hydroxysteroid dehydrogenase activities from Clostridium perfringens.

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