Browsing by Author "Hainline, Bryan E."

Now showing 1 - 7 of 7
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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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    Breakage in the SNRPN locus in a balanced 46,XY,t(15;19) Prader-Willi syndrome patient
    (Oxford Academic, 1996-04) Sun, Yongming; Nicholls, Robert D.; Butler, Merlin G.; Saitoh, Shinji; Hainline, Bryan E.; Palmer, Catherine G.; Medical and Molecular Genetics, School of Medicine
    A patient with Prader-Willi syndrome (PWS) was found to carry a de novo balanced reciprocal translocation, t(15;19)(q12;q13.41), which disrupted the small nuclear ribonucleoprotein N (SNRPN) locus. The translocation chromosome 15 was found to be paternal in origin. Uniparental disomy and abnormal DNA methylation were ruled out. The translocation breakpoint was found to have occurred between exon 0 (second exon) and 1 (third exon) of the SNRPN locus outside of the SmN open reading frame (ORF), which is intact. The transcriptional activities of ZNF127, IPW, PAR-1, and PAR-5 were detected with RT-PCR from fibroblasts of the patient, suggesting that these genes may not play a significant role in the PWS phenotype in this patient. Transcription from the first two exons and last seven exons of the SNRPN gene was also detected with RT-PCR; however, the complete mRNA (10 exons) was not detected. Thus, the PWS phenotype in the patient is likely to be the result of disruption of the SNRPN locus.
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    Consideration of a metabolic disorder in the differential of mild developmental delay: A case of nonketotic hyperglycinemia revisited 36 years later
    (Wiley, 2021-03-31) Tramontana, Timothy F.; Wilson, Theodore E.; Hainline, Bryan E.; Medical and Molecular Genetics, School of Medicine
    We present a 53‐year‐old male with nonketotic hyperglycinemia (NKH) who presented in decompensated state to our university hospital several months prior to a primary diagnosis of multifocal pneumonia accompanied by reports of seizure‐like activity, altered mental status, tremors, and fever. He was initially diagnosed with NKH in his preschool years, over 40 years previously, along with his younger sister. At that time, he had developmental and physical delays (which his sister also experienced). His health course has been relatively uneventful otherwise, as regards decompensation of his disease, and he has not been on the standard regimens of reduced dietary glycine intake along with dextromethorphan and sodium benzoate. Recent molecular confirmation of NKH was completed and both he and his sibling likely have an attenuated form of NKH mediated by the combined effects of their variants. This paper presents what we believe to be report of the oldest surviving individuals with attenuated NKH.
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    Diffusion-Weighted Imaging of White Matter Abnormalities in Patients with Phenylketonuria
    (American Society of Neuroradiology, 2001-09) Phillips, Micheal D.; McGraw, Peter; Lowe, Mark J.; Mathews, Vincent P.; Hainline, Bryan E.; Radiology and Imaging Sciences, School of Medicine
    Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (EC 1.14.16.1). Affected patients develop elevated plasma and tissue levels of phenylalanine and its related ketoacids. Untreated patients usually exhibit severe mental retardation and poor motor function, with characteristic T2 white matter signal abnormalities on conventional MR images. In the present study, we performed diffusion-weighted imaging in three PKU patients. All three patients demonstrated significantly restricted diffusion in all white matter areas examined.
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    Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
    (Elsevier, 2022) Stephenson, Sarah E.M.; Costain, Gregory; Blok, Laura E.R.; Silk, Michael A.; Nguyen, Thanh Binh; Dong, Xiaomin; Alhuzaimi, Dana E.; Dowling, James J.; Walker, Susan; Amburgey, Kimberly; Hayeems, Robin Z.; Rodan, Lance H.; Schwartz, Marc A.; Picker, Jonathan; Lynch, Sally A.; Gupta, Aditi; Rasmussen, Kristen J.; Schimmenti, Lisa A.; Klee, Eric W.; Niu, Zhiyv; Agre, Katherine E.; Chilton, Ilana; Chung, Wendy K.; Revah-Politi, Anya; Au, P.Y. Billie; Griffith, Christopher; Racobaldo, Melissa; Raas-Rothschild, Annick; Zeev, Bruria Ben; Barel, Ortal; Moutton, Sebastien; Morice-Picard, Fanny; Carmignac, Virginie; Cornaton, Jenny; Marle, Nathalie; Devinsky, Orrin; Stimach, Chandler; Burns Wechsler, Stephanie; Hainline, Bryan E.; Sapp, Katie; Willems, Marjolaine; Bruel, Ange-Line; Dias, Kerith-Rae; Evans, Carey-Anne; Roscioli, Tony; Sachdev, Rani; Temple, Suzanna E.L.; Zhu, Ying; Baker, Joshua J.; Scheffer, Ingrid E.; Gardiner, Fiona J.; Schneider, Amy L.; Muir, Alison M.; Mefford, Heather C.; Crunk, Amy; Heise, Elizabeth M.; Millan, Francisca; Monaghan, Kristin G.; Person, Richard; Rhodes, Lindsay; Richards, Sarah; Wentzensen, Ingrid M.; Cogné, Benjamin; Isidor, Bertrand; Nizon, Mathilde; Vincent, Marie; Besnard, Thomas; Piton, Amelie; Marcelis, Carlo; Kato, Kohji; Koyama, Norihisa; Ogi, Tomoo; Suk-Ying Goh, Elaine; Richmond, Christopher; Amor, David J.; Boyce, Jessica O.; Morgan, Angela T.; Hildebrand, Michael S.; Kaspi, Antony; Bahlo, Melanie; Friðriksdóttir, Rún; Katrínardóttir, Hildigunnur; Sulem, Patrick; Stefánsson, Kári; Björnsson, Hans Tómas; Mandelstam, Simone; Morleo, Manuela; Mariani, Milena; TUDP Study Group; Scala, Marcello; Accogli, Andrea; Torella, Annalaura; Capra, Valeria; Wallis, Mathew; Jansen, Sandra; Weisfisz, Quinten; de Haan, Hugoline; Sadedin, Simon; Broad Center for Mendelian Genomics; Lim, Sze Chern; White, Susan M.; Ascher, David B.; Schenck, Annette; Lockhart, Paul J.; Christodoulou, John; Tan, Tiong Yang; Medical and Molecular Genetics, School of Medicine
    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.
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    TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila
    (Elsevier, 2021) Goodman, Lindsey D.; Cope, Heidi; Nil, Zelha; Ravenscroft, Thomas A.; Charng, Wu-Lin; Lu, Shenzhao; Tien, An-Chi; Pfundt, Rolph; Koolen, David A.; Haaxma, Charlotte A.; Veenstra-Knol, Hermine E.; Klein Wassink-Ruiter, Jolien S.; Wevers, Marijke R.; Jones, Melissa; Walsh, Laurence E.; Klee, Victoria H.; Theunis, Miel; Legius, Eric; Steel, Dora; Barwick, Katy E.S.; Kurian, Manju A.; Mohammad, Shekeeb. S.; Dale, Russell C.; Terhal, Paulien A.; van Binsbergen, Ellen; Kirmse, Brian; Robinette, Bethany; Cogné, Benjamin; Isidor, Bertrand; Grebe, Theresa A.; Kulch, Peggy; Hainline, Bryan E.; Sapp, Katherine; Morava, Eva; Klee, Eric W.; Macke, Erica L.; Trapane, Pamela; Spencer, Christopher; Si, Yue; Begtrup, Amber; Moulton, Matthew J.; Dutta, Debdeep; Kanca, Oguz; Undiagnosed Diseases Network; Wangler, Michael F.; Yamamoto, Shinya; Bellen, Hugo J.; Tan, Queenie K.G.; Pediatrics, School of Medicine
    Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.
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    Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
    (Elsevier, 2021-05) Muir, Alison M.; Gardner, Jennifer F.; van Jaarsveld, Richard H.; de Lange, Iris M.; van der Smagt, Jasper J.; Wilson, Golder N.; Dubbs, Holly; Goldberg, Ethan M.; Zitano, Lia; Bupp, Caleb; Martinez, Jose; Srour, Myriam; Accogli, Andrea; Alhakeem, Afnan; Meltzer, Meira; Gropman, Andrea; Brewer, Carole; Caswell, Richard C.; Montgomery, Tara; McKenna, Caoimhe; McKee, Shane; Powell, Corinna; Vasudevan, Pradeep C.; Brady, Angela F.; Joss, Shelagh; Tysoe, Carolyn; Noh, Grace; Tarnopolsky, Mark; Brady, Lauren; Zafar, Muhammad; Schrier Vergano, Samantha A.; Murray, Brianna; Sawyer, Lindsey; Hainline, Bryan E.; Sapp, Katherine; DeMarzo, Danielle; Huismann, Darcy J.; Wentzensen, Ingrid M.; Schnur, Rhonda E.; Monaghan, Kristin G.; Juusola, Jane; Rhodes, Lindsay; Dobyns, William B.; Lecoquierre, Francois; Goldenberg, Alice; Polster, Tilman; Axer-Schaefer, Susanne; Platzer, Konrad; Klöckner, Chiara; Hoffman, Trevor L.; MacArthur, Daniel G.; O'Leary, Melanie C.; VanNoy, Grace E.; England, Eleina; Varghese, Vinod C.; Mefford, Heather C.; Medical and Molecular Genetics, School of Medicine
    Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.