Browsing by Author "Matyakhina, Ludmila"

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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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    Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome
    (Biomed Central, 2019-03-25) Vetrini, Francesco; McKee, Shane; Rosenfeld, Jill A.; Suri, Mohnish; Lewis, Andrea M.; Nugent, Kimberly Margaret; Roeder, Elizabeth; Littlejohn, Rebecca O.; Holder, Sue; Zhu, Wenmiao; Alaimo, Joseph T.; Graham, Brett; Harris, Jill M.; Gibson, James B.; Pastore, Matthew; McBride, Kim L.; Komara, Makanko; Al-Gazali, Lihadh; Al Shamsi, Aisha; Fanning, Elizabeth A.; Wierenga, Klaas J.; Scott, Daryl A.; Ben-Neriah, Ziva; Meiner, Vardiella; Cassuto, Hanoch; Elpeleg, Orly; Lloyd Holder Jr, J.; Burrage, Lindsay C.; Seaver, Laurie H.; Van Maldergem, Lionel; Mahida, Sonal; Soul, Janet S.; Marlatt, Margaret; Matyakhina, Ludmila; Vogt, Julie; Gold, June-Anne; Park, Soo-Mi; Varghese, Vinod; Lampe, Anne K.; Kumar, Ajith; Lees, Melissa; Holder-Espinasse, Muriel; McConnell, Vivienne; Bernhard, Birgitta; Blair, Ed; Harrison, Victoria; Muzny, Donna M.; Gibbs, Richard A.; Elsea, Sarah H.; Posey, Jennifer E.; Bi, Weimin; Lalani, Seema; Xia, Fan; Yang, Yaping; Eng, Christine M.; Lupski, James R.; Liu, Pengfei; Medical and Molecular Genetics, School of Medicine
    It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.
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    De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome
    (BMC, 2019-02-28) Vetrini, Francesco; McKee, Shane; Rosenfeld, Jill A.; Suri, Mohnish; Lewis, Andrea M.; Nugent, Kimberly Margaret; Roeder, Elizabeth; Littlejohn, Rebecca O.; Holder, Sue; Zhu, Wenmiao; Alaimo, Joseph T.; Graham, Brett; Harris, Jill M.; Gibson, James B.; Pastore, Matthew; McBride, Kim L.; Komara, Makanko; Al-Gazali, Lihadh; Al Shamsi, Aisha; Fanning, Elizabeth A.; Wierenga, Klaas J.; Scott, Daryl A.; Ben-Neriah, Ziva; Meiner, Vardiella; Cassuto, Hanoch; Elpeleg, Orly; Holder, J. Lloyd, Jr.; Burrage, Lindsay C.; Seaver, Laurie H.; Van Maldergem, Lionel; Mahida, Sonal; Soul, Janet S.; Marlatt, Margaret; Matyakhina, Ludmila; Vogt, Julie; Gold, June-Anne; Park, Soo-Mi; Varghese, Vinod; Lampe, Anne K.; Kumar, Ajith; Lees, Melissa; Holder-Espinasse, Muriel; McConnell, Vivienne; Bernhard, Birgitta; Blair, Ed; Harrison, Victoria; The DDD study; Muzny, Donna M.; Gibbs, Richard A.; Elsea, Sarah H.; Posey, Jennifer E.; Bi, Weimin; Lalani, Seema; Xia, Fan; Yang, Yaping; Eng, Christine M.; Lupski, James R.; Liu, Pengfei; Medical and Molecular Genetics, School of Medicine
    BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.