Review

. 2020 Dec;8(12):e1544.

doi: 10.1002/mgg3.1544. Epub 2020 Nov 7.

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Laura E Meissner¹, Ellen F Macnamara², Precilla D'Souza^{1

2}, John Yang², Gilbert Vezina³; Undiagnosed Diseases Network⁴; Carlos R Ferreira⁵, Wadih M Zein⁶, Cynthia J Tifft^{1

2}, David R Adams^{1

2}

Collaborators, Affiliations

Collaborators

Undiagnosed Diseases Network:
Maria T Acosta, Margaret Adam, David R Adams, Pankaj B Agrawal, Mercedes E Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A Ashley, Mahshid S Azamian, Carlos A Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Heather A Colley, Cynthia M Cooper, Heidi Cope, William J Craigen, Andrew B Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G Dayal, Matthew Deardorff, Esteban C Dell'Angelica, Shweta U Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D Douine, David D Draper, Laura Duncan, Dawn Earl, David J Eckstein, Lisa T Emrick, Christine M Eng, Cecilia Esteves, Tyra Estwick, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L Fieg, Laurie C Findley, Paul G Fisher, Brent L Fogel, Irman Forghani, Laure Fresard, William A Gahl, Ian Glass, Rena A Godfrey, Katie Golden-Grant, Alica M Goldman, David B Goldstein, Alana Grajewski, Catherine A Groden, Andrea L Gropman, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Jean M Johnston, Lefkothea Karaviti, Emily G Kelley, Jennifer Kennedy, Dana Kiley, Isaac S Kohane, Jennefer N Kohler, Deborah Krakow, Donna M Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B Krier, Seema R Lalani, Byron Lam, Christina Lam, Brendan C Lanpher, Ian R Lanza, C Christopher Lau, Kimberly LeBlanc, Brendan H Lee, Hane Lee, Roy Levitt, Richard A Lewis, Sharyn A Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, Bryan Mak, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Rong Mao, Kenneth Maravilla, Thomas C Markello, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Elisabeth McGee, Heather Mefford, J Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M Moretti, Marie Morimoto, John J Mulvihill, David R Murdock, Mariko Nakano-Okuno, Avi Nath, Stan F Nelson, John H Newman, Sarah K Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, John A Phillips 3rd, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey, Aaron Quinlan, Wendy Raskind, Archana N Raja, Deepak A Rao, Genecee Renteria, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Natalie Rosenwasser, Maura Ruzhnikov, Ralph Sacco, Jacinda B Sampson, Susan L Samson, Mario Saporta, C Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A Scott, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H Sillari, Edwin K Silverman, Janet S Sinsheimer, Kathy Sisco, Edward C Smith, Kevin S Smith, Emily Solem, Lilianna Solnica-Krezel, Rebecca C Spillmann, Joan M Stoler, Nicholas Stong, Jennifer A Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Cecelia P Tamburro, Queenie K-G Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Brianna M Tucker, Tiina K Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Stephanie Wallace, Nicole M Walley, Chris A Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-Kai Wang, Michael F Wangler, Patricia A Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Jeremy D Woods, Shinya Yamamoto, John Yang, Guoyun Yu, Diane B Zastrow, Chunli Zhao, Stephan Zuchner

Affiliations

¹ Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
² Undiagnosed Diseases Program, The Common Fund, NIH, Bethesda, MD, USA.
³ Division of Diagnostic Imaging and Radiology, Children's National Health System, Washington, DC, USA.
⁴ Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
⁵ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.

PMID: 33159716
PMCID: PMC7767569
DOI: 10.1002/mgg3.1544

Review

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Laura E Meissner et al. Mol Genet Genomic Med. 2020 Dec.

. 2020 Dec;8(12):e1544.

doi: 10.1002/mgg3.1544. Epub 2020 Nov 7.

Authors

Collaborators

Undiagnosed Diseases Network:
Maria T Acosta, Margaret Adam, David R Adams, Pankaj B Agrawal, Mercedes E Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A Ashley, Mahshid S Azamian, Carlos A Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Heather A Colley, Cynthia M Cooper, Heidi Cope, William J Craigen, Andrew B Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G Dayal, Matthew Deardorff, Esteban C Dell'Angelica, Shweta U Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D Douine, David D Draper, Laura Duncan, Dawn Earl, David J Eckstein, Lisa T Emrick, Christine M Eng, Cecilia Esteves, Tyra Estwick, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L Fieg, Laurie C Findley, Paul G Fisher, Brent L Fogel, Irman Forghani, Laure Fresard, William A Gahl, Ian Glass, Rena A Godfrey, Katie Golden-Grant, Alica M Goldman, David B Goldstein, Alana Grajewski, Catherine A Groden, Andrea L Gropman, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Jean M Johnston, Lefkothea Karaviti, Emily G Kelley, Jennifer Kennedy, Dana Kiley, Isaac S Kohane, Jennefer N Kohler, Deborah Krakow, Donna M Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B Krier, Seema R Lalani, Byron Lam, Christina Lam, Brendan C Lanpher, Ian R Lanza, C Christopher Lau, Kimberly LeBlanc, Brendan H Lee, Hane Lee, Roy Levitt, Richard A Lewis, Sharyn A Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, Bryan Mak, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Rong Mao, Kenneth Maravilla, Thomas C Markello, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Elisabeth McGee, Heather Mefford, J Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M Moretti, Marie Morimoto, John J Mulvihill, David R Murdock, Mariko Nakano-Okuno, Avi Nath, Stan F Nelson, John H Newman, Sarah K Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, John A Phillips 3rd, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey, Aaron Quinlan, Wendy Raskind, Archana N Raja, Deepak A Rao, Genecee Renteria, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Natalie Rosenwasser, Maura Ruzhnikov, Ralph Sacco, Jacinda B Sampson, Susan L Samson, Mario Saporta, C Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A Scott, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H Sillari, Edwin K Silverman, Janet S Sinsheimer, Kathy Sisco, Edward C Smith, Kevin S Smith, Emily Solem, Lilianna Solnica-Krezel, Rebecca C Spillmann, Joan M Stoler, Nicholas Stong, Jennifer A Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Cecelia P Tamburro, Queenie K-G Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Brianna M Tucker, Tiina K Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Stephanie Wallace, Nicole M Walley, Chris A Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-Kai Wang, Michael F Wangler, Patricia A Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Jeremy D Woods, Shinya Yamamoto, John Yang, Guoyun Yu, Diane B Zastrow, Chunli Zhao, Stephan Zuchner

Affiliations

¹ Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
² Undiagnosed Diseases Program, The Common Fund, NIH, Bethesda, MD, USA.
³ Division of Diagnostic Imaging and Radiology, Children's National Health System, Washington, DC, USA.
⁴ Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
⁵ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.

PMID: 33159716
PMCID: PMC7767569
DOI: 10.1002/mgg3.1544

Abstract

Background: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined.

Methods and results: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband.

Conclusion: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.

Keywords: DYRK1A; Down syndrome; autosomal dominant mental retardation 7; feeding difficulties; microcephaly.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**FIGURE 1**
Magnetic resonance imaging of the brain. (a) sagittal and (b) coronal plane showing widened cerebral subarachnoid space, cerebral ventriculomegaly, and generalized mild cerebral cortex volume loss

**FIGURE 2**
(a) and (b) Proband 1 at 2 years, 7 months. Image displays typical facial gestalt including microtia, deeply set eyes, thin upper lip vermilion, flat philtrum, and triangular face. (c) and (d) Proband 2 at 12 years, 8 months. Image displays narrow facies, low‐set ears with cupped right ear and simple deformed helix on the left, mild hypertelorism, and mid‐face malar hypoplasia

See this image and copyright information in PMC

References

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DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Collaborators

Affiliations

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Authors

Collaborators

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Abstract

Conflict of interest statement

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