Browsing by Subject "Developmental disorders"

Now showing 1 - 3 of 3
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    A cross-disorder dosage sensitivity map of the human genome
    (Elsevier, 2022) Collins, Ryan L.; Glessner, Joseph T.; Porcu, Eleonora; Lepamets, Maarja; Brandon, Rhonda; Lauricella, Christopher; Han, Lide; Morley, Theodore; Niestroj, Lisa-Marie; Ulirsch, Jacob; Everett, Selin; Howrigan, Daniel P.; Boone, Philip M.; Fu, Jack; Karczewski, Konrad J.; Kellaris, Georgios; Lowther, Chelsea; Lucente, Diane; Mohajeri, Kiana; Nõukas, Margit; Nuttle, Xander; Samocha, Kaitlin E.; Trinh, Mi; Ullah, Farid; Võsa, Urmo; Epi25 Consortium; Estonian Biobank Research Team; Hurles, Matthew E.; Aradhya, Swaroop; Davis, Erica E.; Finucane, Hilary; Gusella, James F.; Janze, Aura; Katsanis, Nicholas; Matyakhina, Ludmila; Neale, Benjamin M.; Sanders, David; Warren, Stephanie; Hodge, Jennelle C.; Lal, Dennis; Ruderfer, Douglas M.; Meck, Jeanne; Mägi, Reedik; Esko, Tõnu; Reymond, Alexandre; Kutalik, Zoltán; Hakonarson, Hakon; Sunyaev, Shamil; Brand, Harrison; Talkowski, Michael E.; Medical and Molecular Genetics, School of Medicine
    Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
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    Mother–infant interaction in women with depression in pregnancy and in women with a history of depression: the Psychiatry Research and Motherhood – Depression (PRAM-D) study
    (Cambridge University Press, 2021-05-25) Bind, Rebecca H.; Biaggi, Alessandra; Bairead, Aoife; Du Preez, Andrea; Hazelgrove, Katie; Waites, Freddie; Conroy, Susan; Dazzan, Paola; Osborne, Sarah; Pawlby, Susan; Sethna, Vaheshta; Pariante, Carmine M.; Psychiatry, School of Medicine
    Background: Little is known about the effects of depression before birth on the quality of the mother-infant interaction. Aims: To understand whether depression, either in pregnancy or in lifetime before pregnancy, disrupts postnatal mother-infant interactions. Method: We recruited 131 pregnant women (51 healthy, 52 with major depressive disorder (MDD) in pregnancy, 28 with a history of MDD but healthy pregnancy), at 25 weeks' gestation. MDD was confirmed with the Structured Clinical Interview for DSM-IV Disorders. Neonatal behaviour was assessed at 6 days with the Neonatal Behavioural Assessment Scale, and mother-infant interaction was assessed at 8 weeks and 12 months with the Crittenden CARE-Index. Results: At 8 weeks and 12 months, dyads in the depression and history-only groups displayed a reduced quality of interaction compared with healthy dyads. Specifically, at 8 weeks, 62% in the depression group and 56% in the history-only group scored in the lowest category of dyadic synchrony (suggesting therapeutic interventions are needed), compared with 37% in the healthy group (P = 0.041); 48% and 32%, respectively, scored the same at 12 months, compared with 14% in the healthy group (P = 0.003). At 6 days, neonates in the depression and history-only groups exhibited decreased social-interactive behaviour, which, together with maternal socioeconomic difficulties, was also predictive of interaction quality, whereas postnatal depression was not. Conclusions: Both antenatal depression and a lifetime history of depression are associated with a decreased quality of mother-infant interaction, irrespective of postnatal depression. Clinicians should be aware of this, as pregnancy provides an opportunity for identification and intervention to support the developing relationship.
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    Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
    (Springer Nature, 2022-10-26) Fulton, Sasha L.; Wenderski, Wendy; Lepack, Ashley E.; Eagle, Andrew L.; Fanutza, Tomas; Bastle, Ryan M.; Ramakrishnan, Aarthi; Hays, Emma C.; Neal, Arianna; Bendl, Jaroslav; Farrelly, Lorna A.; Al-Kachak, Amni; Lyu, Yang; Cetin, Bulent; Chan, Jennifer C.; Tran, Tina N.; Neve, Rachael L.; Roper, Randall J.; Brennand, Kristen J.; Roussos, Panos; Schimenti, John C.; Friedman, Allyson K.; Shen, Li; Blitzer, Robert D.; Robison, Alfred J.; Crabtree, Gerald R.; Maze, Ian; Biology, School of Science
    With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.