Abstract
| Original language | English |
|---|---|
| Article number | jmg-2022-109127 |
| Pages (from-to) | 1092-1104 |
| Number of pages | 13 |
| Journal | Journal of medical genetics |
| Volume | 60 |
| Issue number | 11 |
| Early online date | 2023 |
| DOIs | |
| Publication status | Published - 1 Nov 2023 |
Keywords
- Congenital, Hereditary, and Neonatal Diseases and Abnormalities
- Genetics, Medical
- Genomics
- Immune System Diseases
- Sequence Analysis, DNA
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In: Journal of medical genetics, Vol. 60, No. 11, jmg-2022-109127, 01.11.2023, p. 1092-1104.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
AU - Mohajeri, Arezoo
AU - Vaseghi-Shanjani, Maryam
AU - Rosenfeld, Jill A.
AU - Yang, Gui Xiang
AU - Lu, Henry
AU - Sharma, Mehul
AU - Lin, Susan
AU - Salman, Areesha
AU - Waqas, Meriam
AU - Sababi Azamian, Mahshid
AU - Worley, Kim C.
AU - del Bel, Kate L.
AU - Kozak, Frederick K.
AU - Rahmanian, Ronak
AU - Biggs, Catherine M.
AU - Hildebrand, Kyla J.
AU - Lalani, Seema R.
AU - Nicholas, Sarah K.
AU - Scott, Daryl A.
AU - Mostafavi, Sara
AU - van Karnebeek, Clara
AU - Henkelman, Erika
AU - Halparin, Jessica
AU - Yang, Connie L.
AU - Armstrong, Linlea
AU - Turvey, Stuart E.
AU - Lehman, Anna
AU - Acosta, Maria T.
AU - Adam, Margaret
AU - Adams, David R.
AU - Alvarez, Raquel L.
AU - Alvey, Justin
AU - Amendola, Laura
AU - Andrews, Ashley
AU - Ashley, Euan A.
AU - Bacino, Carlos A.
AU - Bademci, Guney
AU - Balasubramanyam, Ashok
AU - Baldridge, Dustin
AU - Bale, Jim
AU - Bamshad, Michael
AU - Barbouth, Deborah
AU - Bayrak-Toydemir, Pinar
AU - Beck, Anita
AU - Beggs, Alan H.
AU - Behrens, Edward
AU - Bejerano, Gill
AU - Bellen, Hugo J.
AU - Bennett, Jimmy
AU - Berg-Rood, Beverly
AU - Bernstein, Jonathan A.
AU - Berry, Gerard T.
AU - Bican, Anna
AU - Bivona, Stephanie
AU - Blue, Elizabeth
AU - Bohnsack, John
AU - Bonner, Devon
AU - Botto, Lorenzo
AU - Boyd, Brenna
AU - Briere, Lauren C.
AU - Brokamp, Elly
AU - Brown, Gabrielle
AU - Burke, Elizabeth A.
AU - Burrage, Lindsay C.
AU - Butte, Manish J.
AU - Byers, Peter
AU - Byrd, William E.
AU - Carey, John
AU - Carrasquillo, Olveen
AU - Cassini, Thomas
AU - Chang, Ta Chen Peter
AU - Chanprasert, Sirisak
AU - Chao, Hsiao-Tuan
AU - Clark, Gary D.
AU - Coakley, Terra R.
AU - Cobban, Laurel A.
AU - Cogan, Joy D.
AU - Coggins, Matthew
AU - Sessions Cole, F.
AU - Colley, Heather A.
AU - Cooper, Cynthia M.
AU - Cope, Heidi
AU - Corona, Rosario
AU - Craigen, William J.
AU - Crouse, Andrew B.
AU - Cunningham, Michael
AU - D'Souza, Precilla
AU - Dai, Hongzheng
AU - Dasari, Surendra
AU - Davis, Joie
AU - Dayal, Jyoti G.
AU - Dell'Angelica, Esteban C.
AU - Dipple, Katrina
AU - Doherty, Daniel
AU - Dorrani, Naghmeh
AU - Doss, Argenia L.
AU - Douine, Emilie D.
AU - Duncan, Laura
AU - Earl, Dawn
AU - Eckstein, David J.
AU - Emrick, Lisa T.
AU - Eng, Christine M.
AU - Falk, Marni
AU - Fieg, Elizabeth L.
AU - Fisher, Paul G.
AU - Fogel, Brent L.
AU - Forghani, Irman
AU - Gahl, William A.
AU - Glass, Ian
AU - Gochuico, Bernadette
AU - Goddard, Page C.
AU - Godfrey, Rena A.
AU - Golden-Grant, Katie
AU - Grajewski, Alana
AU - Hadley, Don
AU - Hahn, Sihoun
AU - Halley, Meghan C.
AU - Hamid, Rizwan
AU - Hassey, Kelly
AU - Hayes, Nichole
AU - High, Frances
AU - Hing, Anne
AU - Hisama, Fuki M.
AU - Holm, Ingrid A.
AU - Hom, Jason
AU - Horike-Pyne, Martha
AU - Huang, Alden
AU - Hutchison, Sarah
AU - Introne, Wendy
AU - Isasi, Rosario
AU - Izumi, Kosuke
AU - Jamal, Fariha
AU - Jarvik, Gail P.
AU - Jarvik, Jeffrey
AU - Jayadev, Suman
AU - Jean-Marie, Orpa
AU - Jobanputra, Vaidehi
AU - Karaviti, Lefkothea
AU - Kennedy, Jennifer
AU - Ketkar, Shamika
AU - Kiley, Dana
AU - Kilich, Gonench
AU - Kobren, Shilpa N.
AU - Kohane, Isaac S.
AU - Kohler, Jennefer N.
AU - Korrick, Susan
AU - Kozuira, Mary
AU - Krakow, Deborah
AU - Krasnewich, Donna M.
AU - Kravets, Elijah
AU - Lalani, Seema R.
AU - Lam, Byron
AU - Lam, Christina
AU - Lanpher, Brendan C.
AU - Lanza, Ian R.
AU - LeBlanc, Kimberly
AU - Lee, Brendan H.
AU - Levitt, Roy
AU - Lewis, Richard A.
AU - Liu, Pengfei
AU - Liu, Xue Zhong
AU - Longo, Nicola
AU - Loo, Sandra K.
AU - Loscalzo, Joseph
AU - Maas, Richard L.
AU - Macnamara, Ellen F.
AU - MacRae, Calum A.
AU - Maduro, Valerie V.
AU - Mahoney, Rachel
AU - Malicdan, May Christine V.
AU - Mamounas, Laura A.
AU - Manolio, Teri A.
AU - Mao, Rong
AU - Maravilla, Kenneth
AU - Marom, Ronit
AU - Marth, Gabor
AU - Martin, Beth A.
AU - Martin, Martin G.
AU - Martinez-Agosto, Julian A.
AU - Marwaha, Shruti
AU - McCauley, Jacob
AU - McConkie-Rosell, Allyn
AU - McCray, Alexa T.
AU - McGee, Elisabeth
AU - Mefford, Heather
AU - Merritt, J. Lawrence
AU - Might, Matthew
AU - Mirzaa, Ghayda
AU - Morava, Eva
AU - Moretti, Paolo
AU - Mulvihill, John
AU - Nakano-Okuno, Mariko
AU - Nelson, Stanley F.
AU - Newman, John H.
AU - Nicholas, Sarah K.
AU - Nickerson, Deborah
AU - Nieves-Rodriguez, Shirley
AU - Novacic, Donna
AU - Oglesbee, Devin
AU - Orengo, James P.
AU - Pace, Laura
AU - Pak, Stephen
AU - Pallais, J. Carl
AU - Palmer, Christina G. S.
AU - Papp, Jeanette C.
AU - Parker, Neil H.
AU - Phillips, John A.
AU - Posey, Jennifer E.
AU - Potocki, Lorraine
AU - Pusey Swerdzewski, Barbara N.
AU - Quinlan, Aaron
AU - Rao, Deepak A.
AU - Raper, Anna
AU - Raskind, Wendy
AU - Renteria, Genecee
AU - Reuter, Chloe M.
AU - Rives, Lynette
AU - Robertson, Amy K.
AU - Rodan, Lance H.
AU - Rosenfeld, Jill A.
AU - Rosenwasser, Natalie
AU - Rossignol, Francis
AU - Ruzhnikov, Maura
AU - Sacco, Ralph
AU - Sampson, Jacinda B.
AU - Saporta, Mario
AU - Schaechter, Judy
AU - Schedl, Timothy
AU - Schoch, Kelly
AU - Scott, Daryl A.
AU - Scott, C. Ron
AU - Shashi, Vandana
AU - Shin, Jimann
AU - Silverman, Edwin K.
AU - Sinsheimer, Janet S.
AU - Sisco, Kathy
AU - Smith, Edward C.
AU - Smith, Kevin S.
AU - Solem, Emily
AU - Solnica-Krezel, Lilianna
AU - Solomon, Ben
AU - Spillmann, Rebecca C.
AU - Stoler, Joan M.
AU - Sullivan, Kathleen
AU - Sullivan, Jennifer A.
AU - Sun, Angela
AU - Sutton, Shirley
AU - Sweetser, David A.
AU - Sybert, Virginia
AU - Tabor, Holly K.
AU - Tan, Queenie K. -G.
AU - Tan, Amelia L. M.
AU - Tekin, Mustafa
AU - Telischi, Fred
AU - Thorson, Willa
AU - Tifft, Cynthia J.
AU - Toro, Camilo
AU - Tran, Alyssa A.
AU - Ungar, Rachel A.
AU - Urv, Tiina K.
AU - Vanderver, Adeline
AU - Velinder, Matt
AU - Viskochil, Dave
AU - Vogel, Tiphanie P.
AU - Wahl, Colleen E.
AU - Walker, Melissa
AU - Wallace, Stephanie
AU - Walley, Nicole M.
AU - Wambach, Jennifer
AU - Wan, Jijun
AU - Wang, Lee-Kai
AU - Wangler, Michael F.
AU - Ward, Patricia A.
AU - Wegner, Daniel
AU - Hubshman, Monika Weisz
AU - Wener, Mark
AU - Wenger, Tara
AU - Westerfield, Monte
AU - Wheeler, Matthew T.
AU - Whitlock, Jordan
AU - Wolfe, Lynne A.
AU - Xiao, Changrui
AU - Yamamoto, Shinya
AU - Yang, John
AU - Zhang, Zhe
AU - Zuchner, Stephan
AU - Boycott, Kym
AU - Brudno, Michael
AU - Bernier, Francois
AU - Dyment, David
AU - Kernohan, Kristin
AU - Innes, Micheil
AU - Lamont, Ryan
AU - Parboosingh, Jillian
AU - Marshall, Deborah
AU - Marshall, Christian
AU - Mendoza, Roberto
AU - Dowling, James
AU - Hayeems, Robin
AU - Knoppers, Bartha
N1 - Funding Information: MV-S is funded by the Vanier Canada Graduate Scholarship (Vanier CGS) and the University of British Columbia Four Year Doctoral Fellowship (4YF). CMB holds a Health Professional-Investigator award from Michael Smith Health Research BC and is supported by the Providence Healthcare Research Institute Early Career Investigator award. ST holds a Translational Research Grant Award from the Jeffrey Modell Foundation, a Tier 1 Canada Research Chair in Pediatric Precision Health, and the Aubrey J. Tingle Professor of Pediatric Immunology. ST and CMB hold a Project Grant from the Canadian Institutes of Health Research (PJT 178054). Part of this work was funded by a joint award held by AL, CvK and SM from Genome Canada, Genome BC, and BC Children’s Hospital Research Institute (F17-04161). Additionally, research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007709. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2023 Author(s). Published by BMJ.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Background: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. Methods: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. Results: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136-Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. Conclusion: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.
AB - Background: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. Methods: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. Results: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136-Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. Conclusion: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.
KW - Congenital, Hereditary, and Neonatal Diseases and Abnormalities
KW - Genetics, Medical
KW - Genomics
KW - Immune System Diseases
KW - Sequence Analysis, DNA
UR - http://www.scopus.com/inward/record.url?scp=85164492346&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jmg-2022-109127
DO - https://doi.org/10.1136/jmg-2022-109127
M3 - Article
C2 - 37316189
SN - 0022-2593
VL - 60
SP - 1092
EP - 1104
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 11
M1 - jmg-2022-109127
ER -