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Gillentine MA, Wang T, Hoekzema K, et al. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med. 2021;13(1):63doi: 10.1186/s13073-021-00870-6.
Gillentine, M. A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P., Guo, H., Kim, C. N., De Vries, B. B. A., Vissers, L. E. L. M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C. A., Bhat, G., Cobian, K., Bird, L. M., Friedman, J., Wright, M. S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C. K., White, K. M., Elpeleg, O., Berger, I., Espineli, E. J., Fagerberg, C., Brasch-Andersen, C., Hansen, L. K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L. M., Mckee, S., Mirzaa, G. M., Muss, C., Pappas, J., Peeters, H., Romano, C., Elia, M., Galesi, O., Simon, M. E. H., van Gassen, K. L. I., Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I. V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R. K., Nowakowski, T., Bernier, R. A., & Eichler, E. E. (2021). Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome medicine, 13(1), 63. https://doi.org/10.1186/s13073-021-00870-6
Gillentine, Madelyn A, et al. "Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders." Genome medicine vol. 13,1 (2021): 63. doi: https://doi.org/10.1186/s13073-021-00870-6
Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, Kim CN, De Vries BBA, Vissers LELM, Nordenskjold M, Kvarnung M, Lindstrand A, Nordgren A, Gecz J, Iascone M, Cereda A, Scatigno A, Maitz S, Zanni G, Bertini E, Zweier C, Schuhmann S, Wiesener A, Pepper M, Panjwani H, Torti E, Abid F, Anselm I, Srivastava S, Atwal P, Bacino CA, Bhat G, Cobian K, Bird LM, Friedman J, Wright MS, Callewaert B, Petit F, Mathieu S, Afenjar A, Christensen CK, White KM, Elpeleg O, Berger I, Espineli EJ, Fagerberg C, Brasch-Andersen C, Hansen LK, Feyma T, Hughes S, Thiffault I, Sullivan B, Yan S, Keller K, Keren B, Mignot C, Kooy F, Meuwissen M, Basinger A, Kukolich M, Philips M, Ortega L, Drummond-Borg M, Lauridsen M, Sorensen K, Lehman A, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K, Earl RK, Nowakowski T, Bernier RA, Eichler EE. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med. 2021 Apr 19;13(1):63. doi: 10.1186/s13073-021-00870-6. PMID: 33874999; PMCID: PMC8056596.
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Genome Med. 2021 Apr 19;13(1):63. doi: 10.1186/s13073-021-00870-6.

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Genome medicine

Madelyn A Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N Kim, Bert B A De Vries, Lisenka E L M Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A Bacino, Gifty Bhat, Katherine Cobian, Lynne M Bird, Jennifer Friedman, Meredith S Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K Christensen, Kerry M White, Orly Elpeleg, Itai Berger, Edward J Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L Manace Benman, Shane Mckee, Ghayda M Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E H Simon, Koen L I van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, Rachel K Earl, Tomasz Nowakowski, Raphael A Bernier, Evan E Eichler

Affiliations

  1. Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, Seattle, WA, 981095-5065, USA.
  2. Baylor Genetics Laboratories, Houston, TX, USA.
  3. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  4. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  5. Department of Anatomy, University of California, San Francisco, CA, USA.
  6. Department of Psychiatry, University of California, San Francisco, CA, USA.
  7. Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA.
  8. The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
  9. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  10. Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  11. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  12. School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
  13. Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
  14. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  15. Laboratorio di Genetica Medica - ASST Papa Giovanni XXIII, Bergamo, Italy.
  16. Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
  17. Genetic Unit, Department of Pediatrics, Fondazione MBBM S. Gerardo Hospital, Monza, Italy.
  18. Unit of Neuromuscular and Neurodegenerative Disorders, Department Neurosciences, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.
  19. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
  20. Center on Human Development and Disability, University of Washington, Seattle, WA, USA.
  21. Seattle Children's Autism Center, Seattle, WA, USA.
  22. GeneDX, Gaithersburg, MD, USA.
  23. Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA.
  24. Texas Children's Hospital, Houston, TX, USA.
  25. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  26. The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA.
  27. Department of Pediatrics, Section of Genetics, University of Illinois at Chicago, Chicago, IL, USA.
  28. Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
  29. Genetics/Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA, USA.
  30. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  31. Department of Neurosciences, University of California San Diego, San Diego, CA, USA.
  32. Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium.
  33. Clinique de Génétique, Hôpital Jeanne de Flandre, Bâtiment Modulaire, CHU, 59037, Lille Cedex, France.
  34. Sorbonne Universités, Centre de Référence déficiences intellectuelles de causes rares, département de génétique et embryologie médicale, Hôpital Trousseau, AP-HP, Paris, France.
  35. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
  36. Department of Medical and Molecular Genetics, IU Health, Indianapolis, IN, USA.
  37. Department of Genetics, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
  38. Pediatric Neurology, Assuta-Ashdod University Hospital, Ashdod, Israel.
  39. Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel.
  40. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  41. H C Andersen Chilldrens Hospital, Odense University Hospital, Odense, Denmark.
  42. Gillette Children's Specialty Healthcare, Saint Paul, MN, USA.
  43. Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO, USA.
  44. The University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA.
  45. Children's Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, MO, USA.
  46. Oregon Health & Science University, Corvallis, OR, USA.
  47. Department of Genetics, Hópital Pitié-Salpêtrière, Paris, France.
  48. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  49. Genetics Department, Cook Children's Hospital, Fort Worth, TX, USA.
  50. Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
  51. BC Children's Hospital and BC Women's Hospital, Vancouver, BC, Canada.
  52. Division of Developmental Pediatrics, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
  53. Sunny Hill Health Centre for Children, Vancouver, BC, Canada.
  54. Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, NY, USA.
  55. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  56. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
  57. UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  58. Kaiser Permanente Southern California, Los Angeles, CA, USA.
  59. The Permanente Medical Group, Oakland, CA, USA.
  60. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
  61. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  62. Department of Pediatrics, University of Washington, Seattle, WA, USA.
  63. Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
  64. Al Dupont Hospital for Children, Wilmington, DE, USA.
  65. NYU Grossman School of Medicine, Department of Pediatrics, Clinical Genetic Services, New York, NY, USA.
  66. Center for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
  67. Oasi Research Institute-IRCCS, Troina, Italy.
  68. Department of Genetics, University Medical Center, Utrecht University, Utrecht, The Netherlands.
  69. Rare Disease Institute, Children's National Health System, Washington, DC, USA.
  70. Department of Genetics, Driscoll Children's Hospital, Corpus Christi, TX, USA.
  71. Department of Pediatric Gastroenterology, Driscoll Children's Hospital, Corpus Christi, TX, USA.
  72. Àrea de Genètica Clínica i Molecular, Hospital Vall d'Hebrón, Barcelona, Spain.
  73. Centre de référence Anomalies du développement, CHU Grenoble-Alpes, Grenoble, France.
  74. UF Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne and INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, F-21000, Dijon, France.
  75. INSERM UMR 1231 Génétique des Anomalies du Développement, Université Bourgogne Franche-Comté, Dijon, France.
  76. Centre de Référence Maladies Rares « déficience intellectuelle », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  77. Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes malformatifs »? Université Bourgogne Franche-Comté, Dijon, France.
  78. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  79. Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, Seattle, WA, 981095-5065, USA. [email protected].
  80. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. [email protected].

PMID: 33874999 PMCID: PMC8056596 DOI: 10.1186/s13073-021-00870-6

Abstract

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Keywords: Cortex development; Gene families; Neurodevelopmental disorders; hnRNPs

References

  1. Coe BP, Stessman HAF, Sulovari A, Geisheker MR, Bakken TE, Lake AM, et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat Genet. 2019;51(1):106–16. - PubMed
  2. Khalil B, Morderer D, Price PL, Liu F, Rossoll W. mRNP assembly, axonal transport, and local translation in neurodegenerative diseases. Brain Res. 2018;1693(Pt A):75–91. - PubMed
  3. Purice MD, Taylor JP. Linking hnRNP function to ALS and FTD pathology. Front Neurosci. 2018;12 - PubMed
  4. Fu X-D, Ares M. Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet. 2014;15(10):689–701. - PubMed
  5. Dickerson JE, Robertson DL. On the origins of Mendelian disease genes in man: the impact of gene duplication. Mol Biol Evol. 2012;29(1):61–9. - PubMed
  6. Chen W-H, Zhao X-M, van Noort V, Bork P. Human monogenic disease genes have frequently functionally redundant paralogs. PLoS Comput Biol. 2013;16:9(5). - PubMed
  7. Lal D, May P, Perez-Palma E, Samocha KE, Kosmicki JA, Robinson EB, et al. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders. Genome Med. 2020;12(1):1–12. - PubMed
  8. Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495(7442):467–73. - PubMed
  9. Le Ber I, Van Bortel I, Nicolas G, Bouya-Ahmed K, Camuzat A, Wallon D, et al. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with “multisystem proteinopathy” and frontotemporal lobar degeneration phenotypes. Neurobiol Aging. 2014;35(4):934.e5–934.e6. - PubMed
  10. Bhoj E, Halbach S, McDonald-McGinn D, Tan C, Lande R, Waggoner D, et al. Expanding the spectrum of microdeletion 4q21 syndrome: a partial phenotype with incomplete deletion of the minimal critical region and a new association with cleft palate and Pierre Robin sequence. Am J Med Genet A. 2013;161(9):2327–33. - PubMed
  11. Reichert SC, Li R, Turner SA, van Jaarsveld RH, Massink MPG, van den Boogaard M-JH, et al. HNRNPH1-related syndromic intellectual disability: seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome. Clin Genet. 2020;98(1):91–8. - PubMed
  12. Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, et al. Variants in HNRNPH2 on the X chromosome are associated with a neurodevelopmental disorder in females. Am J Hum Genet. 2016;99(3):728–34. - PubMed
  13. Au PYB, Goedhart C, Ferguson M, Breckpot J, Devriendt K, Wierenga K, et al. Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature. Eur J Hum Genet EJHG. 2018;26(9):1272–81. - PubMed
  14. Okamoto N. Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation. Am J Med Genet A. 2019;179(5):822–6. - PubMed
  15. Dentici ML, Barresi S, Niceta M, Pantaleoni F, Pizzi S, Dallapiccola B, et al. Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency. Clin Genet. 2018;93(2):401–7. - PubMed
  16. Lange L, Pagnamenta AT, Lise S, Clasper S, Stewart H, Akha ES, et al. A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia. Clin Genet. 2016;90(3):258–62. - PubMed
  17. Miyake N, Inaba M, Mizuno S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N A case of atypical kabuki syndrome arising from a novel missense variant in HNRNPK. Clin Genet. 2017;92(5):554–5. - PubMed
  18. Duijkers FA, McDonald A, Janssens GE, Lezzerini M, Jongejan A, van Koningsbruggen S, et al. HNRNPR variants that impair Homeobox gene expression drive developmental disorders in humans. Am J Hum Genet. 2019;104(6):1040–59. - PubMed
  19. Engwerda A, Frentz B, den Ouden AL, Flapper BCT, Swertz MA, Gerkes EH, et al. The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports. Eur J Hum Genet. 2018;26(10):1478–89. - PubMed
  20. Depienne C, Nava C, Keren B, Heide S, Rastetter A, Passemard S, et al. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Hum Genet. 2017;136(4):463–79. - PubMed
  21. Yates TM, Vasudevan PC, Chandler KE, Donnelly DE, Stark Z, Sadedin S, Willoughby J, Broad Center for Mendelian Genomics, DDD study, Balasubramanian M. De novo mutations in HNRNPU result in a neurodevelopmental syndrome. Am J Med Genet A. 2017;173(11):3003–12. - PubMed
  22. Bramswig NC, Lüdecke H-J, Hamdan FF, Altmüller J, Beleggia F, Elcioglu NH, et al. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability. Hum Genet. 2017;136(7):821–34. - PubMed
  23. Leduc MS, Chao H-T, Qu C, Walkiewicz M, Xiao R, Magoulas P, et al. Clinical and molecular characterization of de novo loss of function variants in HNRNPU. Am J Med Genet A. 2017;173(10):2680–9. - PubMed
  24. Turner TN, Yi Q, Krumm N, Huddleston J, Hoekzema K, F Stessman HA, et al. denovo-db: a compendium of human de novo variants. Nucleic Acids Res. 2017;45(D1):D804–11. - PubMed
  25. Harmsen S, Buchert R, Mayatepek E, Haack TB, Distelmaier F. Bain type of X-linked syndromic mental retardation in boys. Clin Genet. 2019;95(6):734–5. - PubMed
  26. Jepsen WM, Ramsey K, Szelinger S, Llaci L, Balak C, Belnap N, Bilagody C, de Both M, Gupta R, Naymik M, Pandey R, Piras IS, Sanchez-Castillo M, Rangasamy S, Narayanan V, Huentelman MJ. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. Clin Genet. 2019;96(2):183–5. - PubMed
  27. Pilch J, Koppolu AA, Walczak A, Murcia Pienkowski VA, Biernacka A, Skiba P, et al. Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation. Clin Genet. 2018;94(3–4):381–5. - PubMed
  28. Somashekar PH, Narayanan DL, Jagadeesh S, Suresh B, Vaishnavi RD, Bielas S, et al. Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2. Am J Med Genet A. 2020;182(1):183–8. - PubMed
  29. denovo-db. Available from: http://denovo-db.gs.washington.edu - PubMed
  30. Durkin A, Albaba S, Fry AE, Morton JE, Douglas A, Beleza A, Williams D, Volker-Touw CML, Lynch SA, Canham N, Clowes V, Straub V, Lachlan K, Gibbon F, el Gamal M, Varghese V, Parker MJ, Newbury-Ecob R, Turnpenny PD, Gardham A, Ghali N, Balasubramanian M. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review. Am J Med Genet A. 2020;182(7):1637–54. - PubMed
  31. Caliebe A, Kroes HY, van der Smagt JJ, Martin-Subero JI, Tönnies H, Van ‘t Slot R, et al. Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene. Eur J Med Genet. 2010;53(4):179–85. - PubMed
  32. de Kovel CGF, Brilstra EH, van Kempen MJA, Van’t Slot R, Nijman IJ, Afawi Z, et al. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Mol Genet Genomic Med. 2016;4(5):568–80. - PubMed
  33. Demos M, Guella I, DeGuzman C, McKenzie MB, Buerki SE, Evans DM, et al. Diagnostic yield and treatment impact of targeted exome sequencing in early-onset epilepsy. Front Neurol. 2019;10:434. - PubMed
  34. Stessman HAF, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, Shaw M, Gecz J, Anderlid BM, Nordgren A, Lindstrand A, Schwartz C, Kooy RF, Vandeweyer G, Helsmoortel C, Romano C, Alberti A, Vinci M, Avola E, Giusto S, Courchesne E, Pramparo T, Pierce K, Nalabolu S, Amaral DG, Scheffer IE, Delatycki MB, Lockhart PJ, Hormozdiari F, Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier RA, Eichler EE. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49(4):515–26. - PubMed
  35. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–15. - PubMed
  36. Yuen RK, Merico D, Bookman M, L Howe J, Thiruvahindrapuram B, Patel RV, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci 2017;20(4):602–611. - PubMed
  37. Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, Leal SM, Bernier R, Eichler EE. Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015;47(6):582–8. - PubMed
  38. Lelieveld SH, Reijnders MRF, Pfundt R, Yntema HG, Kamsteeg E-J, de Vries P, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19(9):1194–6. - PubMed
  39. Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217–21. - PubMed
  40. Hinokuma N, Nakashima M, Asai H, Nakamura K, Akaboshi S, Fukuoka M, et al. Clinical and genetic characteristics of patients with Doose syndrome. Epilepsia Open. - PubMed
  41. Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med Off J Am Coll Med Genet. 2016;18(9):898–905. - PubMed
  42. Feliciano P, Zhou X, Astrovskaya I, Turner TN, Wang T, Brueggeman L, et al. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes. NPJ Genomic Med. 2019;4(1):19.  - PubMed
  43. Yamada M, Shiraishi Y, Uehara T, Suzuki H, Takenouchi T, Abe-Hatano C, et al. Diagnostic utility of integrated analysis of exome and transcriptome: successful diagnosis of Au-Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities. Mol Genet Genomic Med. 2020;8(9):e1364. - PubMed
  44. Peron A, Novara F, Briola FL, Merati E, Giannusa E, Segalini E, et al. Missense variants in the Arg206 residue of HNRNPH2: further evidence of causality and expansion of the phenotype. Am J Med Genet A. 2020;182(4):823–8. - PubMed
  45. Borlot F, de Almeida BI, Combe SL, Andrade DM, Filloux FM, Myers KA. Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability. Epilepsia. 2019;60(8):1661–9. - PubMed
  46. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30. - PubMed
  47. Chérot E, Keren B, Dubourg C, Carré W, Fradin M, Lavillaureix A, et al. Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of 2 clinical units and 216 patients. Clin Genet. 2018;93(3):567–76. - PubMed
  48. Coppola A, Cellini E, Stamberger H, Saarentaus E, Cetica V, Lal D, et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia. 2019;60(4):689–706. - PubMed
  49. The Epilepsy Genetics Initiative. Systematic reanalysis of diagnostic exomes increases yield. Epilepsia. 2019;60(5):797–806. - PubMed
  50. Hamdan FF, Srour M, Capo-Chichi J-M, Daoud H, Nassif C, Patry L, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10(10):e1004772. - PubMed
  51. Johannesen KM, Nikanorova N, Marjanovic D, Pavbro A, Larsen LHG, Rubboli G, et al. Utility of genetic testing for therapeutic decision-making in adults with epilepsy. Epilepsia. 2020;61(6):1234–9. - PubMed
  52. Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53(8):511–22. - PubMed
  53. Monroe GR, Frederix GW, Savelberg SMC, de Vries TI, Duran KJ, van der Smagt JJ, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med Off J Am Coll Med Genet. 2016;18(9):949–56. - PubMed
  54. Oates S, Tang S, Rosch R, Lear R, Hughes EF, Williams RE, et al. Incorporating epilepsy genetics into clinical practice: a 360°evaluation. Npj Genomic Med. 2018;3(1):1–11. - PubMed
  55. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94(5):677–94. - PubMed
  56. Stamouli S, Anderlid B-M, Willfors C, Thiruvahindrapuram B, Wei J, Berggren S, et al. Copy number variation analysis of 100 twin pairs enriched for neurodevelopmental disorders. Twin Res Hum Genet. 2018;21(1):1–11. - PubMed
  57. Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu Y-F, McSweeney KM, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med Off J Am Coll Med Genet. 2015;17(10):774–81. - PubMed
  58. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8. - PubMed
  59. Maystadt I, Deprez M, Moortgat S, Benoît V, Karadurmus D. A second case of Okamoto syndrome caused by HNRNPK mutation. Am J Med Genet A. 2020;182(6):1537–9. - PubMed
  60. Shimada S, Oguni H, Otani Y, Nishikawa A, Ito S, Eto K, Nakazawa T, Yamamoto-Shimojima K, Takanashi JI, Nagata S, Yamamoto T. An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU. Brain Dev. 2018;40(9):813–8. - PubMed
  61. Wang T, Hoekzema K, Vecchio D, Wu H, Sulovari A, Coe BP, et al. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nat Commun. 2020;11(1):4932. - PubMed
  62. Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature. 2020;586(7831):757–62. - PubMed
  63. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An J-Y, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell. 2020;180(3):568–84. e23 - PubMed
  64. Iourov IY, Zelenova MA, Vorsanova SG, Voinova VV, Yurov YB. 4q21.2q21.3 duplication: molecular and neuropsychological aspects. Curr Genomics. 2018;19(3):173–8. - PubMed
  65. Lebedev IN, Nazarenko LP, Skryabin NA, Babushkina NP, Kashevarova AA. A de novo microtriplication at 4q21.21-q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech. Am J Med Genet A. 2016;170(8):2089–96. - PubMed
  66. Zarrei M, Merico D, Kellam B, Engchuan W, Scriver T, Jokhan R, Wilson MD, Parr J, Lemire EG, Stavropoulos DJ, Scherer SW. A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome. Am J Med Genet A. 2017;173(5):1287–93.  - PubMed
  67. Mohamed AM, El-Bassyouni HT, El-Gerzawy AM, Hammad SA, Helmy NA, Kamel AK, et al. Cytogenomic characterization of 1q43q44 deletion associated with 4q32.1q35.2 duplication and phenotype correlation. Mol Cytogenet. 2018;11:57. - PubMed
  68. Stessman HA, Bernier R, Eichler EE. A genotype-first approach to defining the subtypes of a complex disease. Cell. 2014;156(5):872–7. - PubMed
  69. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–9. - PubMed
  70. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. ArXiv:12073907 [q-bio.GN] 2012. https://arxiv.org/abs/1207.3907 . - PubMed
  71. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–303. - PubMed
  72. Danecek P, McCarthy SA. BCFtools/csq: haplotype-aware variant consequences. Bioinformatics. 2017;33(13):2037–9. - PubMed
  73. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928–30. - PubMed
  74. NHGRI/NHLBI University of Washington-Center for Mendelian Genomics (UW-CMG), Seattle, WA. MyGene2. Available from: http://www.mygene2.org - PubMed
  75. Abramovs N, Brass A, Tassabehji M. GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize disease candidate genes. Nat Genet. 2020;52(1):35–9. - PubMed
  76. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485(7397):246–50. - PubMed
  77. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46(9):944–50. - PubMed
  78. Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C. MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat. 2019;40(8):1030–8. - PubMed
  79. Meyer MJ, Beltrán JF, Liang S, Fragoza R, Rumack A, Liang J, et al. Interactome INSIDER: a structural interactome browser for genomic studies. Nat Methods. 2018;15(2):107–14. - PubMed
  80. Turner TN, Douville C, Kim D, Stenson PD, Cooper DN, Chakravarti A, Karchin R. Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns. Hum Mol Genet. 2015;24(21):5995–6002. - PubMed
  81. Coban-Akdemir Z, White JJ, Song X, Jhangiani SN, Fatih JM, Gambin T, et al. Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. Am J Hum Genet. 2018;103(2):171–87. - PubMed
  82. Shamsani J, Kazakoff SH, Armean IM, McLaren W, Parsons MT, Thompson BA, O’Mara TA, Hunt SE, Waddell N, Spurdle AB. A plugin for the Ensembl variant effect predictor that uses MaxEntScan to predict variant spliceogenicity. Bioinformatics. 2019;35(13):2315–7. - PubMed
  83. Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016;135(8):851–67. - PubMed
  84. Nowakowski TJ, Bhaduri A, Pollen AA, Alvarado B, Mostajo-Radji MA, Di Lullo E, et al. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science. 2017;358(6368):1318–23. - PubMed
  85. CSEA tool. Available from: http://genetics.wustl.edu/jdlab/csea-tool-2/ - PubMed
  86. Babbi G, Martelli PL, Casadio R. PhenPath: a tool for characterizing biological functions underlying different phenotypes. BMC Genomics. 2019;20(8):548. - PubMed
  87. gnomAD. Available from: https://gnomad.broadinstitute.org/ - PubMed
  88. Huelga SC, Vu AQ, Arnold JD, Liang TY, Liu PP, Yan BY, et al. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 2012;1(2):167–78. - PubMed
  89. Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM, Shaw PJ. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol (Berl). 2015;130(1):63–75.  - PubMed
  90. Mohagheghi F, Prudencio M, Stuani C, Cook C, Jansen-West K, Dickson DW, Petrucelli L, Buratti E. TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. Hum Mol Genet. 2016;25(3):534–45. - PubMed
  91. Kashima T, Rao N, David CJ, Manley JL. hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum Mol Genet. 2007;16(24):3149–59. - PubMed
  92. Berson A, Barbash S, Shaltiel G, Goll Y, Hanin G, Greenberg DS, et al. Cholinergic-associated loss of hnRNP-A/B in Alzheimer’s disease impairs cortical splicing and cognitive function in mice. EMBO Mol Med. 2012;4(8):730–42. - PubMed
  93. Borreca A, Gironi K, Amadoro G, Ammassari-Teule M. Opposite dysregulation of fragile-X mental retardation protein and heteronuclear ribonucleoprotein C protein associates with enhanced APP translation in Alzheimer disease. Mol Neurobiol. 2016;53(5):3227–34. - PubMed
  94. Sun Y, Chen H, Lu Y, Duo J, Lei L, OuYang Y, et al. Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain. J Neurol. 2019;266(2):498–506. - PubMed
  95. Mori K, Lammich S, Mackenzie IRA, Forné I, Zilow S, Kretzschmar H, et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol (Berl). 2013;125(3):413–23. - PubMed
  96. Lee EK, Kim HH, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran SS, et al. hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol. 2010;17(6):732–9. - PubMed
  97. Moursy A, Allain FH-T, Cléry A. Characterization of the RNA recognition mode of hnRNP G extends its role in SMN2 splicing regulation. Nucleic Acids Res. 2014;42(10):6659–72. - PubMed
  98. Barbash S, Garfinkel BP, Maoz R, Simchovitz A, Nadorp B, Guffanti A, et al. Alzheimer’s brains show inter-related changes in RNA and lipid metabolism. Neurobiol Dis. 2017;106:1–13. - PubMed
  99. Cho S, Moon H, Loh TJ, Oh HK, Cho S, Choy HE, et al. hnRNP M facilitates exon 7 inclusion of SMN2 pre-mRNA in spinal muscular atrophy by targeting an enhancer on exon 7. Biochim Biophys Acta. 2014;1839(4):306–15. - PubMed
  100. Waibel S, Neumann M, Rabe M, Meyer T, Ludolph AC. Novel missense and truncating mutations in FUS/TLS in familial ALS. Neurology. 2010;75(9):815–7. - PubMed
  101. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11. - PubMed
  102. Chen H-H, Chang J-G, Lu R-M, Peng T-Y, Tarn W-Y. The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Mol Cell Biol. 2008;28(22):6929–38. - PubMed
  103. Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M. Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons. PLoS One. 2014;9(10):e110846. - PubMed
  104. Guo H, Duyzend MH, Coe BP, Baker C, Hoekzema K, Gerdts J, et al. Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Genet Med. 2019;21(7):1611–1620. A. - PubMed
  105. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216–21. - PubMed
  106. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet Lond Engl. 2012;380(9854):1674–82. - PubMed
  107. Ernst C. Proliferation and differentiation deficits are a major convergence point for neurodevelopmental disorders. Trends Neurosci. 2016 [cited 2020 Feb 12];39(5):290–9. - PubMed
  108. Donovan APA, Basson MA. The neuroanatomy of autism – a developmental perspective. J Anat. 2017;230(1):4–15. - PubMed
  109. Guarnieri FC, de Chevigny A, Falace A, Cardoso C. Disorders of neurogenesis and cortical development. Dialogues Clin Neurosci. 2018;20(4):255–66. - PubMed
  110. Wang Y-C, Chang K-C, Lin B-W, Lee J-C, Lai C-H, Lin L-J, et al. The EGF/hnRNP Q1 axis is involved in tumorigenesis via the regulation of cell cycle-related genes. Exp Mol Med. 2018;50(6):70. - PubMed
  111. Chun Y, Kim R, Lee S. Centromere protein (CENP)-W interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) U and may contribute to kinetochore-microtubule attachment in mitotic cells. PLoS One. 2016;11(2):e0149127. - PubMed
  112. Douglas P, Ye R, Morrice N, Britton S, Trinkle-Mulcahy L, Lees-Miller SP. Phosphorylation of SAF-A/hnRNP-U serine 59 by Polo-like kinase 1 is required for mitosis. Mol Cell Biol. 2015;35(15):2699–713. - PubMed
  113. Sugimasa H, Taniue K, Kurimoto A, Takeda Y, Kawasaki Y, Akiyama T. Heterogeneous nuclear ribonucleoprotein K upregulates the kinetochore complex component NUF2 and promotes the tumorigenicity of colon cancer cells. Biochem Biophys Res Commun. 2015;459(1):29–35. - PubMed
  114. Al-Khalaf HH, Colak D, Al-Saif M, Al-Bakheet A, Hendrayani S-F, Al-Yousef N, et al. p16INK4A positively regulates Cyclin D1 and E2F1 through negative control of AUF1. PLoS One. 2011;6(7):e21111. - PubMed
  115. Schuetze M, Park MTM, Cho IY, MacMaster FP, Chakravarty MM, Bray SL. Morphological alterations in the thalamus, striatum, and pallidum in autism spectrum disorder. Neuropsychopharmacology. 2016;41(11):2627–37. - PubMed
  116. Peixoto RT, Chantranupong L, Hakim R, Levasseur J, Wang W, Merchant T, et al. Abnormal striatal development underlies the early onset of behavioral deficits in Shank3B−/− mice. Cell Rep. 2019;29(7):2016–27. e4 - PubMed
  117. Schumann CM, Bauman MD, Amaral DG. Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders. Neuropsychologia. 2011;49(4):745–59. - PubMed
  118. Pérez-Palma E, May P, Iqbal S, Niestroj L-M, Du J, Heyne HO, et al. Identification of pathogenic variant enriched regions across genes and gene families. Genome Res. 2020;30(1):62–71. - PubMed
  119. Dusen CMV, Yee L, McNally LM, McNally MT. A glycine-rich domain of hnRNP H/F promotes nucleocytoplasmic shuttling and nuclear import through an interaction with transportin 1. Mol Cell Biol. 2010;30(10):2552–62. - PubMed
  120. Choi J-H, Kim S-H, Jeong Y-H, Kim SW, Min K-T, Kim K-T. hnRNP Q regulates internal ribosome entry site-mediated fmr1 translation in neurons. Mol Cell Biol. 2019;39(4):e00371–18. - PubMed
  121. Tratnjek L, Živin M, Glavan G. Synaptotagmin 7 and SYNCRIP proteins are ubiquitously expressed in the rat brain and co-localize in Purkinje neurons. J Chem Neuroanat. 2017;79:12–21. - PubMed
  122. Williams KR, McAninch DS, Stefanovic S, Xing L, Allen M, Li W, Feng Y, Mihailescu MR, Bassell GJ. hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting Gap-43 mRNA translation. Mol Biol Cell. 2015;27(3):518–34. - PubMed
  123. McDermott SM, Yang L, Halstead JM, Hamilton RS, Meignin C, Davis I. Drosophila Syncrip modulates the expression of mRNAs encoding key synaptic proteins required for morphology at the neuromuscular junction. RNA N Y N. 2014;20(10):1593–606. - PubMed
  124. Chen H-H, Yu H-I, Chiang W-C, Lin Y-D, Shia B-C, Tarn W-Y. hnRNP Q regulates Cdc42-mediated neuronal morphogenesis. Mol Cell Biol. 2012;32(12):2224–38. - PubMed
  125. Duning K, Buck F, Barnekow A, Kremerskothen J. SYNCRIP, a component of dendritically localized mRNPs, binds to the translation regulator BC200 RNA. J Neurochem. 2008;105(2):351–9. - PubMed
  126. Schneider T, Ziòłkowska B, Gieryk A, Tyminska A, Przewłocki R. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology. 2007;193(4):547–55. - PubMed
  127. Dobi A, Szemes M, Lee C, Palkovits M, Lim F, Gyorgy A, et al. AUF1 is expressed in the developing brain, binds to AT-rich double-stranded DNA, and regulates enkephalin gene expression. J Biol Chem. 2006;281(39):28889–900. - PubMed
  128. Leirer DJ, Iyegbe CO, Di Forti M, Patel H, Carra E, Fraietta S, et al. Differential gene expression analysis in blood of first episode psychosis patients. Schizophr Res. 2019;209:88–97. - PubMed
  129. Servadio M, Manduca A, Melancia F, Leboffe L, Schiavi S, Campolongo P, Palmery M, Ascenzi P, di Masi A, Trezza V. Impaired repair of DNA damage is associated with autistic-like traits in rats prenatally exposed to valproic acid. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2018;28(1):85–96. - PubMed
  130. Hong Z, Jiang J, Ma J, Dai S, Xu T, Li H, Yasui A. The role of hnRPUL1 involved in DNA damage response is related to PARP1. PLoS One. 2013;8(4):e60208. - PubMed
  131. Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Kzhyshkowska J, Dobner T, Taylor AMR, Turnell AS, Stewart GS, Grand RJ, Jackson SP. Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair. Mol Cell. 2012;45(4):505–16.  - PubMed
  132. Markkanen E, Meyer U, Dianov GL. DNA damage and repair in schizophrenia and autism: implications for cancer comorbidity and beyond. Int J Mol Sci 2016;17(6). - PubMed
  133. Lampasona AA, Czaplinski K. Hnrnpab regulates neural cell motility through transcription of Eps8. RNA N Y N. 2019;25(1):45–59. - PubMed
  134. Sinnamon JR, Waddell CB, Nik S, Chen EI, Czaplinski K. Hnrpab regulates neural development and neuron cell survival after glutamate stimulation. RNA N Y N. 2012;18(4):704–19. - PubMed
  135. White R, Gonsior C, Bauer NM, Krämer-Albers E-M, Luhmann HJ, Trotter J. Heterogeneous nuclear ribonucleoprotein (hnRNP) F is a novel component of oligodendroglial RNA transport granules contributing to regulation of myelin basic protein (MBP) synthesis. J Biol Chem. 2012;287(3):1742–54. - PubMed
  136. Chou M-Y, Rooke N, Turck CW, Black DL. hnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. Mol Cell Biol. 1999;19(1):69–77. - PubMed
  137. Latorre E, Torregrossa R, Wood ME, Whiteman M, Harries LW. Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2. Aging. 2018;10(7):1666–81. - PubMed
  138. GenBank Overview. Available from: https://www.ncbi.nlm.nih.gov/genbank/ - PubMed

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