Browsing by Author "Roeder, Elizabeth"

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    Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections
    (Elsevier, 2024) Jeffries, Lauren; Mis, Emily K.; McWalter, Kirsty; Donkervoort, Sandra; Brodsky, Nina N.; Carpier, Jean-Marie; Ji, Weizhen; Ionita, Cristian; Roy, Bhaskar; Morrow, Jon S.; Darbinyan, Armine; Iyer, Krishna; Aul, Ritu B.; Banka, Siddharth; Chao, Katherine R.; Cobbold, Laura; Cohen, Stacey; Custodio, Helena M.; Drummond-Borg, Margaret; Elmslie, Frances; Finanger, Erika; Hainline, Bryan E.; Helbig, Ingo; Hewson, Stacy; Hu, Ying; Jackson, Adam; Josifova, Dragana; Konstantino, Monica; Leach, Meganne E.; Mak, Bryan; McCormick, David; McGee, Elisabeth; Nelson, Stanley; Nguyen, Joanne; Nugent, Kimberly; Ortega, Lucy; Goodkin, Howard P.; Roeder, Elizabeth; Roy, Sani; Sapp, Katie; Saade, Dimah; Sisodiya, Sanjay M.; Stals, Karen; Towner, Shelley; Wilson, William; Deciphering Developmental Disorders; Genomics England Research Consortium; Undiagnosed Disease Network; Khokha, Mustafa K.; Bönnemann, Carsten G.; Lucas, Carrie L.; Lakhani, Saquib A.; Medical and Molecular Genetics, School of Medicine
    Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants. Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. Conclusion: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
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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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    Genitourinary Defects Associated with Genomic Deletions in 2p15 Encompassing OTX1
    (Public Library of Science, 2014-09-09) Jorgez, Carolina J.; Rosenfeld, Jill A.; Wilken, Nathan R.; Vangapandu, Hima V.; Sahin, Aysegul; Pham, Dung; Carvalho, Claudia M. B.; Bandholz, Anne; Miller, Amanda; Weaver, David D.; Burton, Barbara; Babu, Deepti; Bamforth, John S.; Wilks, Timothy; Flynn, Daniel P.; Roeder, Elizabeth; Patel, Ankita; Cheung, Sau W.; Lupski, James R.; Lamb, Dolores J.; Medical and Molecular Genetics, School of Medicine
    Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
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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.